Search

International audience; We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n\,=\,147) or at relapse (n\,=\,119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n\,=\,64), thiotepa-busulfan (n\,=\,24), BCNU-etoposide-cytarabine-melphalan (BEAM, n\,=\,36) and thiotepa-busulfan-cyclophosphamide (n\,=\,142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.

Chronic lymphocytic leukemia (CLL) is characterized by significant biologic and clinical heterogeneity. This study was designed to explore CLL B-cells’ proteomic profile in order to identify biologic processes affected at an early stage and during disease evolution as stable or progressive. Purified B cells from 11 untreated CLL patients were tested at two time points by liquid chromatography–tandem mass spectrometry. Patients included in the study evolved to either progressive (n = 6) or stable disease (n = 5). First, at an early stage of the disease (Binet stage A), based on the relative abundance levels of 389 differentially expressed proteins (DEPs), samples were separated into stable and progressive clusters with the main differentiating factor being the RNA splicing pathway. Next, in order to test how the DEPs affect RNA splicing, a RNA-Seq study was conducted showing 4217 differentially spliced genes between the two clusters. Distinct longitudinal evolutions were observed with predominantly proteomic modifications in the stable CLL group and spliced genes in the progressive CLL group. Splicing events were shown to be six times more frequent in the progressive CLL group. The main aberrant biologic processes controlled by DEPs and spliced genes in the progressive group were cytoskeletal organization, Wnt/β-catenin signaling, and mitochondrial and inositol phosphate metabolism with a downstream impact on CLL B-cell survival and migration. This study suggests that proteomic profiles at the early stage of CLL can discriminate progressive from stable disease and that RNA splicing dysregulation underlies CLL evolution, which opens new perspectives in terms of biomarkers and therapy.

Currently, prognostic models in diffuse large B-cell lymphoma (DLBCL) fail to closely reflect patients' biological, clinical, and survival heterogeneity. We, therefore, assessed the impact of clinical, biological, immunohistochemical (IHC), baseline (0), and interim (after 2 and 4 treatment cycles) PET (PET0, PET2, and PET4) data not yet included in any scoring system on DLBCL outcome. The analysis was conducted on 89 previously untreated adult patients of the Finistere Observatory Cohort (O.Ly.Fin) with documented DLBCL, recruited between January 2010 and December 2017, with progression-free survival (PFS) and overall survival (OS) as primary and secondary endpoints, respectively. Seventy-eight patients were treated with rituximab, cyclophosphamide, hydroxyadriamycin, vincristine, and prednisone (R-CHOP), while 11 received R-dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and hydroxyadriamycin (EPOCH). Patients were followed up until June 20, 2020. On multivariate analysis, Ki67 ≥ 70% on IHC (K), bulky presentation ≥7.5 cm (B), meningeal lymphomatosis (M), and PET0–PET4 ΔSUVmax de novo DLBCL patients.

Advanced age is an independent poor prognostic factor of diffuse large B-cell lymphoma (DLBCL). PMitCEBO (mitoxantrone, cyclophosphamide, etoposide, vincristine, bleomycin, and prednisolone) is an alternative to the cyclophosphamide, doxorubicin, vincristine, and prednisolone regimen to decrease side effects in elderly patients. Many studies have shown prognostic value of an interim FDG PET-CT to predict survival. A recent consensus (ICML, Lugano 2013) has suggested using the 5-point scale Deauville criteria instead of those of the International Harmonization Project (IHP) to visually assess the response on interim PET. The objective of this study was to evaluate the prognostic value of an interim FDG PET-CT in patients older than 60 with treated DLBCL and to compare IHP and 5-PS Deauville visual interpretation to predict survival.Forty-eight patients (mean age 73.2±5.2 years) treated by R-PMitCEBO for DLBCL undergoing FDG PET-CT before and after 3 cycles of treatment were retrospectively included. Event-free survival and overall survival were determined by Kaplan-Meier method and compared with interim PET-CT results using IHP and 5-PS Deauville criteria.Interim PET results using 5-PS Deauville criteria were significantly correlated with EFS (P0.0001) and OS (P=0.001) whereas they were moderately correlated with EFS (P=0.046) and not with OS (P=0.106) using IHP criteria. Two-year EFS and OS rates were 86.5% and 89.2%, respectively, for patients in 1-3 score group, and 27.3% and 36.4%, respectively, for patients in ≥4 score group using the Deauville criteria.Our results confirmed the prognostic value of an interim PET-CT in elderly patients with DLBCL and the better performance of the 5-PS Deauville criteria.

We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n = 147) or at relapse (n = 119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n = 64), thiotepa-busulfan (n = 24), BCNU-etoposide-cytarabine-melphalan (BEAM, n = 36) and thiotepa-busulfan-cyclophosphamide (n = 142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.

Patients with multiple myeloma are generally older and vary in fitness levels, which may influence the clinical benefit of treatment. Patients from the large, phase 3 FIRST trial in newly diagnosed multiple myeloma (NDMM) were retrospectively investigated to determine outcomes based on frailty using scores for age, Charlson Comorbidity Index (CCI), and Eastern Cooperative Oncology Group performance status (ECOG PS), instead of the EQ-5D quality-of-life questionnaire, as previously reported. ECOG PS (n = 1618) was investigated in frailty groups: frail (49%) and nonfrail (51%). Frail patients experienced worse progression-free and overall survival vs nonfrail patients. Prognostic assessment was improved when combining frailty and International Staging System stage (I/II vs III). Frail patients had a higher risk of developing grade 3/4 treatment-emergent adverse events. Treatment effects observed in the FIRST trial were confirmed per frailty group and per frailty and ISS group. The use of this ECOG PS–containing frailty scale as a predictive measure of clinical outcomes in patients with transplant-ineligible NDMM is supported by data from the FIRST trial. This score, based on age, CCI, and ECOG PS, can be easily replicated and may help design future myeloma studies in frail or nonfrail elderly patients., SCOPUS: ar.j, info:eu-repo/semantics/published

International audience; Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with poor outcomes despite very intensive therapeutic approaches. For the majority of patients which are unfit and treated less intensively, the prognosis is even worse. There has been unspectacular progress in outcome improvement over the last decades and the development of new approaches is of tremendous interest. The tumor microenvironment is credited with an important role in supporting cancer growth, including leukemogenesis. Macrophages are part of the tumor microenvironment and their contribution in this setting is increasingly being deciphered, these cells being credited with a tumor supporting role. Data on macrophage role and polarization in leukemia is scarce. MicroRNAs (miRNAs) have a role in the post-transcriptional regulation of gene expression, by impending translation and promoting degradation of messenger RNAs. They are important modulators of cellular pathways, playing major roles in normal hematopoietic differentiation. miRNA expression is significantly correlated with the prognosis of hematopoietic malignancies, including AML. Oncogenic miRNAs correlate with poor prognosis, while tumor suppressor miRNAs, which inhibit the expression of proto-oncogenes, are correlated with a favorable prognosis. miRNAs are proposed as biomarkers for diagnosis and prognosis and are regarded as therapeutic approaches in many cancers, including AML. miRNAs with epigenetic or modulatory activity, as well as with synergistic activity with chemotherapeutic agents, proved to be promising therapeutic targets in experimental, pre-clinical approaches. The clinical availability of emerging compounds with mimicking or suppressor activity provides the opportunity for future therapeutic targeting of miRNAs. The present paper is focusing on miRNAs which, according to current knowledge, favorably impact on AML outcomes, being regarded as tumor suppressors, and reviews their role in macrophage polarization. We are focusing on miRNA expression in the setting of AML, but data on correlations between miRNA expression and macrophage polarization is mostly coming from studies involving normal tissue.

Richter syndrome (RS) is an aggressive lymphoma arising on the back of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and is the most common B-cell malignancy in the Western world. In the majority of cases, RS presents an activated B cell (ABC) phenotype of diffuse large B-cell lymphoma (DLBCL). From the therapeutic point of view, selective inhibition of PI3Kδ with idelalisib represents a valuable addition to available treatment options for patients with CLL/SLL, many of whom do not respond to or cannot tolerate chemoimmunotherapy. However, to our knowledge, there have been no prospective studies evaluating idelalisib efficacy in a DLBCL-ABC form of RS. Here, we present a case of a DLBCL-ABC form of RS achieving a complete response at 3 weeks after initiating idelalisib and rituximab therapy for six cycles. This response was maintained during the idelalisib monotherapy, but the patient relapsed rapidly after treatment was withdrawn, because of a grade three immune colitis that developed at 10 months of treatment. This report demonstrates that idelalisib is highly effective in RS and provides an attractive option in this aggressive disease. This agent could meet an unmet need by providing a treatment option with a tolerable safety profile for elderly patients with RS.

The purpose of this study was to identify the incidence, causes and impact of non-adherence to oral and subcutaneous chronic treatments for patients with polycythemia vera or essential thrombocythemia. Patients receiving cytoreductive drugs for polycythemia vera or essential thrombocythemia were recruited at our institution (Observatoire Brestois des Néoplasies Myéloprolifératives registry). They completed a one-shot questionnaire designed by investigators (Etude de l’Observance Thérapeutique et des Effets Secondaires des Traitements study). Data about complications (thrombosis, transformation and death) at any time in the patient’s life (before diagnosis, up until consultation and after the completion of the questionnaire) were collected. Sixty-five (22.7%) of 286 patients reported poor adherence (

Background: AcSé Pembrolizumab is a Phase 2, open-label, single-arm, multi-cohort, multicentric study investigating the efficacy and safety of pembrolizumab monotherapy in patients with advanced rare cancers (NCT03012620). Here, we report the first results of Pembrolizumab in the cohort of Primary Central Nervous System Lymphoma (PCNSL). Methods: Main inclusion criteria were: relapsed or refractory PCNSL after one or several lines of treatment including high dose Methotrexate based chemotherapy, pathologically confirmed diffuse large B cell lymphoma, age>18, HIV negative, concurrent steroid medication at a dose no greater than prednisone 20 mg/day or equivalent. Patients received pembrolizumab 200 mg IV as a 30-minute infusion on Day 1 of every 21-day cycles for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to IPCG at 84 day after the start of treatment. Secondary endpoints included best response (ORR), duration of response, progression-free survival (PFS), overall survival (OS), and safety. Analysis used all enrolled patients. Results: 50 patients suffering from PCNSL, including 9 primary vitreoretinal lymphoma (PVRL) were included from July, 2017 to October, 2019. Median age was 72 years (range: 43 to 83), Median PS (ECOG) was 1 (range 0-1). The median number of cycles was 4 (range 1-35). At 84 days from start of treatment, 6 patients responded (4 CR+2PR). Overall, 3 patients whose response was not assessed were considered as failures, and the rates of ORR (CR+PR), stable disease (SD), progressive disease (PD) were 26% (13/50, 8 CR + 5 PR), 10% (5/50), 58% (29/50), respectively. ORR was 29% (12/41) and 11% (1/9) in primary cerebral lymphoma and PVRL respectively. After a median follow-up of 6.7 months (range 0.2-27.4), median PFS was 2.6 months, with 6-month PFS of 29.8% and 6-month OS of 60.4%. In responders, median duration of response was estimated at 10 months (95%CI, 2.7 to 12.5). Grade III and IV toxicities related to the drug were observed in 4 patients (8%) and one patient (2%) respectively. No related toxic death was reported. Conclusion: Pembrolizumab shows moderate activity in relapsed/ refractory PCNSL with acceptable toxicity, supporting further studies evaluating its use in combination therapies. Disclosures Hoang-Xuan: BTG: Consultancy, Research Funding. Houot:Bristol-Myers Squibb: Honoraria; MSD: Honoraria; Gilead: Honoraria; Kite: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Schmitt:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen: Honoraria. Ahle:Roche: Honoraria; Novartis: Honoraria; Biogene: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria. Bories:Abbvie: Consultancy; Celgen: Consultancy; Gilead: Consultancy; BMS: Honoraria; Novartis: Honoraria. Houillier:BTG: Consultancy.

PURPOSE We evaluated the prognostic value of baseline total metabolic tumor volume (TMTV) measured using pretreatment FDG PET for patients with transformation of chronic lymphocytic leukemia (CLL) into diffuse large B-cell lymphoma (DLBCL). METHODS A total of 28 patients with transformation of CLL into DLBCL who had undergone FDG PET before treatment were retrospectively reviewed. Univariate and multivariate analysis of conventional clinicopathologic variables (sex, age, World Health Organization performance status score, International Prognostic Index score, Binet stage, lactate dehydrogenase serum level [LDH], platelet count, presence or not of prior therapies for CLL, the time from CLL to Richter syndrome, Ann Arbor stage, Bulky or not) and metabolic parameters (SUVmax, SUVmean, TMTV, and total lesion glycolysis) at the time of the transformation of CLL into DLBCL were tested for overall survival (OS). RESULTS Of the 28 patients, 14 patients (50%) died during the follow-up period. Low platelet count, World Health Organization performance status score >1, high LDH, and high TMTV were found to be significant prognostic factors for OS on univariate analysis. The 5-year estimates of OS were 63% in the low metabolic burden group (TMTV ≤1200 cm) and 0% in the high metabolic burden group (TMTV >1200 cm). Multivariate analysis revealed that only high LDH was a significant predictor after adjustment for other variables of OS. CONCLUSIONS TMTV extracted from FDG PET at the time of the transformation of CLL into DLBCL is a predictor of OS.

International audience; Approved for the treatment of autoimmune diseases, hematological malignancies, and solid cancers, several monoclonal antibodies (mAb) make use of complement in their mechanism of action. Such an assessment is based on comprehensive investigations that used mouse models, in vitro studies, and analyses from patients at initiation (basal level to highlight deficiencies) and after treatment initiation (mAb impact on complement), which have further provided key insights into the importance of the complement activation and/or complement deficiencies in mAb activity. Accordingly, new approaches can now be developed with the final objective of increasing the clinical efficacy of mAb. These improvements include (i) the concurrent administration of fresh frozen plasma during mAb therapy; (ii) mAb modifications such as immunoglobulin G subclass switching, Fc mutation, or IgG hexamerization to improve the fixation and activation of C1q; (iii) optimization of the target recognition to induce a higher complement-dependent cytotoxicity (CDC) and/or complement-dependant cellular cytotoxicity (CDCC); and (iv) the control of soluble and cellular complement inhibitors.

ObjectiveReal-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL.MethodsThe French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed.ResultsWe identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients 60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis.ConclusionsOur study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.

International audience; Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and the anti-CD20 monoclonal antibody, rituximab, represents the therapeutic gold standard for more than 2 decades in this pathology, when used in combination with chemotherapy. However, some patients experience treatment resistance or rapid relapses, and in particular, those harboring a 17p/TP53 deletion (del(17p)). This resistance could be explained by a chemo-resistance, but it could also result from the direct impact of del(17p) on the pharmacokinetics of rituximab, which represents the aim of the present study. Accordingly, 44 CLL patients were included in the study, and among them 9 presented a del(17p). Next, a total of 233 rituximab sera were selected for a pharmacokinetic study and analyzed in a two-compartment model showing important differences when del(17p) CLL patients were compared with non-del(17p) patients treated with rituximab and chemotherapy: (1) clearance of rituximab was faster; (2) central volume of rituximab distribution V1 (peripheral blood) was reduced while peripheral volume V2 (lymphoid organs and tissues) was increased; and (3) the rate of rituximab elimination (Kout) was faster. In contrast, the group with a better prognosis harboring isolated del(13q) presented a slower rate of elimination (Kout). Pharmacokinetic parameters were independent from the other factors tested such as age, sex, chemotherapy regimen (fludarabine/cyclophosphamide versus bendamustine), IGHV mutational status, and FCGR3A 158VF status. In conclusion, this study provides an additional argument to consider that del(17p) is effective not only to control chemoresistance but also monoclonal antibody activity, based on higher rituximab turnover.

Chronic lymphocytic leukemia (CLL) is the most prevalent type of adult leukemia in Western countries [1]. Despite advances in chemo-immunotherapy, most CLL patients relapse after the first-line che...

Table S1. B cell receptors (BCR) and co-receptors analysis in B-CLL cells (n = 30) according to the capacity of the cells to possess an elevated constitutive Ca2+ entry (CE+) and their capacity to mobilize Ca2+ in response to BCR engagement (IgM+). The phosphorylated phospholipase Cγ2 (pPLCγ2), an immediate downstream BCR effector, was added to the list. Figure S2. Representative kinetic plots of anti-IgM Ca2+ response (A), and thapsigargin (TG) Ca2+ response (B) in representative healthy donor (HD) control B cells (n = 8), CE- B-CLL (n = 13) and CE+ B-CLL (n = 16) samples. Cox regression model of progression free survival (PFS) was used to dichotomize CLL patients in IgM- and IgM+ (dash line). From the TG Ca2+ response analysis, the basal Ca2+ level was evaluated before normalization (1), the TG capacity to release Ca2+ from the endoplasmic reticulum (ER), and the TG capacity to release SOCE following extracellular medium supplementation with 1.8 mM Ca2+. P values are indicated when significant. Figure S3. Basal calcium (Ca2+) entry is related to constitutive calcium entry (CE) but not to store operated Ca2+ entry (SOCE), while the anti-IgM Ca2+ response correlated to thapsigargin (TG) capacity to induce endoplasmic reticulum (ER) Ca2+ release and SOCE. Figure S4. The pool of STIM1 in plasma membrane (STIM1PM) is correlated with basal Ca2+ levels but independent from anti-IgM Ca2+ response and thapsigargin (TG) capacity to release Ca2+ from the endoplasmic reticulum (ER) and to induce SOCE. Correlations between STIM1PM levels with basal Ca2+ (A), anti-IgM Ca2+ response (B), TG capacity to induce ER Ca2+ release (C), and TG SOCE (D). Values were obtained from 18 CLL, see material and methods for details. P and r2 values are indicated when significant. (DOCX 531 kb)

Figure S1. Two pathways control Ca2+ signaling in B cells from patients with chronic lymphocytic leukemia. In the BCR-induced store operated Ca2+ entry pathway, B cell receptor (BCR) interaction with the antigen results in the formation of the signalosome consisting of an active complex composed of the tyrosine kinases Lyn and Syk, B-cell linker protein (BLNK), Bruton-tyrosine-kinase (BTK), phospholipase C gamma 2 (PLCγ2), and phosphatidylinositol-4,5-bisphosphate 3-kinase δ (PI3Kδ) that phosphorylates CD19. Signalosome activation cleaves the membrane phospholipid phosphatidyl inositol 4.5-biphosphate (InsP2) into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (InsP3), which subsequently, through binding to the endoplasmic reticulum (ER) IP3 receptor (InsP3R), mobilizes initially Ca2+ from stores and secondarily extracellular Ca2+ through the interaction between the multimerized reticular stromal interaction molecule 1 (STIM1ER) and the plasma-membrane Orai1 channel. In the constitutive Ca2+ pathway, Ca2+ entry is triggered by STIM1 located at the plasma-membrane (STIM1PM). (PPTX 90 kb)

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, pINTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.FUNDING: F Hoffmann-La Roche.

Objectifs Le syndrome de Richter est un syndrome rare qui consiste au developpement d’un lymphome agressif (le plus souvent un lymphome B diffus a grandes cellules (DLBCL)) chez les patients atteints d’une leucemie lymphoide chronique (LLC). Ce syndrome represente un veritable challenge clinique compte tenu de son pronostic tres reserve. Le caractere clonal du DLBCL identique a la LLC sous-jacente est le principal facteur de mauvais pronostic. Extrait de la TEP au 18FDG, le volume metabolique tumoral total (TMTV) est un parametre pronostique deja connu du DLBCL de novo, du lymphome de Hodgkin et du lymphome folliculaire. L’objectif est d’etudier ici son interet pronostique dans la transformation en DLBCL de la LLC, plus simple a rechercher que le caractere clonal. Materiels et methodes Vingt-quatre patients d’âge median de 72 ans atteints d’un DLBCL compliquant une LLC et ayant beneficie d’une TEP au 18FDG au moment du syndrome de Richter entre janvier 2012 et avril 2018 ont ete analyses retrospectivement. La survie globale a ete calculee par methode de Kaplan–Meier. Pour identifier les facteurs associes a la survie globale, nous avons compare les courbes de survie selon le log-rank test apres binarisation des parametres quantitatifs par extraction d’un cut-off par courbe ROC des parametres demographiques (âge et sexe), cliniques (performans status et score IPI), biologiques (LDH et plaquettes), la presence ou non d’un traitement de la LLC au prealable et les parametres extraits de la TEP au 18FDG (score d’Ann Arbor, caractere bulky ou non, SUVmax, SUVmean et TMTV). Le TMTV a ete mesure par segmentation des SUV des masses tumorales ganglionnaires et extra-ganglionnaires, avec un seuil a 41 % du SUVmax de chaque lesion. Resultats Le delai de suivi median etait de 16 mois avec une survie globale de 75 %. Seuls les taux de plaquettes, de LDH, le score IPI et le TMTV etaient predictifs de la survie globale (respectivement p = 0,001 ; p = 0,001 ; p = 0,0048 ; p = 0,0043) avec respectivement un cut-off de 134000/mm3, 827 UI/L, score 2 et 50 cm3. En analyse multivariee, aucun parametre n’etait significativement associe a la survie globale. Conclusion Un TMTV > 50 cm3 mesure par TEP au 18FDG au moment de la transformation en DLBCL de la LLC serait associe a une survie globale plus faible. Ces resultats sont a confirmer avec un plus grand nombre de patients.

Introduction Limited data is available on the feasibility of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) in elderly patients over 70years of age with non-Hodgkin's lymphoma (NHL). Materials and Methods In the setting of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) group, we retrospectively analyzed 81 consecutive patients with NHL over 70years of age who received AHSCT. Results The median age at AHSCT was 72.3years [70–80]. Patients' were diagnosed with diffuse large B-cell lymphoma (n=40), follicular lymphoma (n=16), mantle cell lymphoma (n=15), T-cell lymphoma (n=5), and other (n=5). Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) was 0 in 73% of patients. Main conditionings were BEAM (Carmustine-Etoposide-Cytarabine-Melphalan, n=61) and melphalan alone (n=14). Median delays to reach 0.5×10 9 /L neutrophils and 20×10 9 /L platelets were of 12 [9–76] days and 12 [0–143] days, respectively. One hundred day and one year cumulative incidence of NRM was 5.4% and 8.5%, respectively. The main cause of death remains relapse. Conclusion In conclusion, this study revealed that AHSCT seemed to be acceptable in patients over 70years of age with NHL. Patient age is not a limiting factor if clinical condition is adequate.

RhuG-CSF reduces the duration of neutropenia induced by chemotherapies. The most frequent drug used for this indication is filgrastim (initially Neupogen®-AMGEN SA). Filgrastim biosimilars have bee...

International audience; Background - The Autorisation Temporaire d'Utilisation (ATU) is an early access program available in France for drugs aimed at treating severe diseases not yet covered by a marketing authorization, for patients without any other therapeutic option and who cannot be included in a clinical trial. Patients and methods - This report presents the use of single-agent ofatumumab in 30 patients with advanced chronic lymphocytic leukemia (CLL) in the French ATU program. Results - These very-high-risk patients had received multiple previous treatments (median = 6), and most had disease that was fludarabine-refractory or alemtuzumab-refractory (or both) or was unsuitable for alemtuzumab treatment. In the intent-to-treat analysis, the overall response rate was 47% (4 of 30, complete response; 10 of 30, partial response). Of 13 patients with 17p deletion, 6 displayed response to ofatumumab, including 2 complete responses. Treatment was well tolerated, with 17 grade 3 or 4 adverse events; 4 cases of grade 3 or 4 infusion reactions were reported, with favorable immediate outcome. Among nonhematologic complications, infections were the most frequent. Conclusion - The results confirm the efficacy and acceptable tolerability profile of ofatumumab as a single agent in severely ill patients with CLL. Attention should be paid to possible early infusion reactions to ofatumumab, as well as to the risk of infection.

Introduction : Les exostoses et les tori sont des excroissances osseuses benignes ayant differentes localisations. Les facteurs intervenant dans leur apparition sont encore discutes. Ces excroissances sont asymptomatiques, mais elles peuvent parfois occasionner differentes genes. De ce fait, leur exerese n’est que rarement necessaire. Observation : Il s’agit d’une femme de 58 ans presentant des exostoses et des tori maxillaires et mandibulaires volumineux, associes a un bruxisme aggrave ayant entraine des attritions occlusales, une baisse de la dimension verticale d’occlusion et des troubles de l’articulation temporo-manbibulaire. Compte tenu du volume des exostoses mandibulaires vestibulaires, une exerese a ete realisee, associee a la confection d’une plaque de liberation occlusale. Commentaires et conclusion : Ce cas interroge sur la part imputable aux surcharges occlusales dans l’apparition d’exostoses. Une revue de la litterature a ete realisee afin de valider cette possible etiologie, de comprendre comment ameliorer la prise en charge et eviter leur reapparition.

International audience; Deregulation of the oxidative cascade of poly-unsaturated fatty acids (PUFAs) has been associated with several cancers, including chronic lymphocytic leukemia (B-CLL). Leukotriene B4 (LTB4), a metabolite of arachidonic acid (AA), is produced by B-CLL and contributes to their survival. The aim of the present study was to analyze the activity of the oxidative cascade of PUFAs in B-CLL. Purified B cells from patients and normal B CD5 positive cells were subjected to flow cytometry, Western-blot and RT-qPCR analyses. LTB4 plasma and intracellular concentrations were determined by ELISA. Our results showed that aggressive B-CLL tumor cells, i.e. cells with an annual proliferation index above 2, over-expressed calcium-dependent and calcium-independent phospholipases A2 (cPLA2-alpha and iPLA2-beta, respectively), 5-lipoxygenase (5LOX) and leukotriene A4 hydroxylase (LTA4H). Intracellular LTB4 levels were lower in the most aggressive cells than in cells with a smaller proliferation index, despite equivalent plasma levels, and lower expression of cytochrome P450 4F3A (CYP4F3A), one major enzyme involved in LTB4 inactivation. Since BLT2, a LTB4 membrane receptor was also more often expressed on aggressive tumor cells, and since a BLT2 inhibitor significantly impaired B-CLL viability in vitro, we propose that LTB4 was efficiently trapped onto BLT2 present on aggressive tumors, thereby eliciting an autocrine response. Taken together our results demonstrate a major deregulation of the pathway leading to LTB4 synthesis and degradation in B-CLL cells, and provide a framework for understanding how these modifications promote cell survival and proliferation, especially in the most aggressive BCLL.

International audience; Cardiac involvement in non-Hodgkin's lymphoma is a rare occurrence with a dismal prognosis, which may evolve with different clinical presentations, the most frequent being heart failure. Diagnosis of cardiac involvement is generally made by cardiac ultrasound. We report a case of lymphomatous pericarditis in the evolution of a non-Hodgkin's lymphoma, diagnosed by PET-CT scan, and occurring concomitantly with complete isotopic remission of enlarged mediastinal lymph nodes following chemotherapy.

International audience; Granulocyte-colony stimulating factors (G-CSFs) enhance bone marrow (BM) recovery after autologous stem cell transplant (ASCT) in patients with lymphoma and myeloma. Few publications exist that discuss the use of filgrastim biosimilars after ASCT. We conducted a single-center retrospective study in patients with lymphoma and myeloma treated at Brest Hospital to assess the cost reductions related to and the efficiency and safety of filgrastim biosimilars. We identified 65 patients with lymphoma or myeloma treated with filgrastim biosimilars for ASCT and compared 19 parameters of these patients, including BM recovery, side effects, infectious complications and treatment costs, with published historical data on a cohort of 50 patients treated with classic filgrastim. We observed a significant reduction of G-CSF costs in both groups but did not observe a change in total hospitalization costs (representing less than 2% of the costs) between groups. Additionally, we did not observe differences between the two groups in BM recovery, infectious complications, side effects or the other studied parameters. In this retrospective study, the absence of differences between groups after ASCT in lymphoma and myeloma led us to believe that these drugs could be safely and effectively used for such indications without a significant impact on hospitalization costs. A prospective study should be conducted to confirm our results.

Primary nodal marginal zone lymphoma (NMZL) is a rare disease. There is no current consensus on how to treat it. The bendamustine plus rituximab (BR) regimen is effective for the treatment of follicular and other indolent lymphomas, but its efficacy in NMZL is not known. We analyzed the outcome of 14 patients diagnosed with NMZL (median age 67 years) who were treated with 375 mg/m

Resume La drepanocytose est une pathologie repandue mais parfois mal apprehendee par les pneumologues qui y sont peu confrontes. Elle merite d’etre connue, compte tenu de sa principale complication respiratoire : le syndrome thoracique aigu (STA). Etat des connaissances La drepanocytose est une maladie autosomique recessive provoquant dans certaines conditions, une falciformation des hematies. Elle touche principalement les individus originaires des pays d’Afrique centrale, de l’ouest et des Antilles. Le STA associe une douleur thoracique ou de la fievre a des infiltrats radiologiques d’apparition recente, chez un individu porteur d’un syndrome drepanocytaire majeur. Ses principales etiologies sont l’infection, l’embolie graisseuse, et l’hypoventilation alveolaire. Il est cependant souvent difficile d’en determiner l’etiologie car il realise un cercle vicieux auto-entretenu. Les bases de la prise en charge, largement sous-evaluees, reposent sur le traitement etiologique, et les mesures visant a eviter l’aggravation liee principalement aux complications, en particulier microcirculatoires, de la maladie. Conclusions Le STA est une complication respiratoire grave de la drepanocytose a laquelle le pneumologue peut etre amene a etre confronte. Une prise en charge adaptee et rapide est necessaire. Les mesures therapeutiques sont simples mais sous-evaluees.

International audience; Intensive treatments like autologous blood stem cell transplantations are standard consolidation treatments for lymphoma and myeloma in young people. The upper age limit for these procedures is constantly increasing. Instead of studying the impact of aging on harvesting peripheral blood stem cells (PBSC), we performed a retrospective study to explore the feasibility of collecting stem cells from patients older than 65 years and compared the efficacy to harvest in younger patients. During a period of 7 years, we identified 108 patients with myeloma or lymphoma who were older than 65 years who underwent PBSC collection. Only eight patients failed to produce a successful harvest. The majority of patients only needed one apheresis (71%). There was a median number of 5.3 x 10(6) CD34+ cells/kg. Our study demonstrated that older patients can also undergo PBSC harvests similar to younger patients.

Objectives: Bone marrow assessment is a diagnostic challenge in staging diffuse large B-cell lymphoma (DLBCL). Diffuse bone marrow uptake (BMU) can be observed on FDG PET/CT performed for initial staging of DLBCL, but remains difficult to analyze. The aim of this study was to evaluate the meaning of this diffuse BMU, and especially to assess its correlation with bone marrow involvement (BMI). Methods: Patients who underwent FDG PET/CT for initial staging of DLBCL were analyzed. Diffuse BMU was assessed using a visual qualitative analysis according to liver uptake (grade 1=below liver uptake, 2=equal to liver uptake, 3=above liver uptake), and a semi-quantitative analysis, by measurement of maximum standardized uptake value (SUV) in the sacral promontory. We compared the BMU with BMI, parameters of disease extension and inflammatory markers. Results: 86 patients (median age 59, range: 19-91, 54 men, 32 women) were included. BMU grade was 1, 2 and 3 in 45, 28 and 13 cases respectively. Bone marrow was considered involved in 13 patients. No statistical correlation was found between diffuse BMU and BMI, using qualitative (p=0.594) or semi-quantitative method (p=0.116). Diffuse BMU visual grading was correlated with inflammatory markers: biological systemic symptoms (p=0.003), CRP (p=0.002) and fibrinogen (p=0.020). Conclusions: Our study suggests that a diffuse BMU seen on FDG PET/CT at initial staging of DLBCL is not representative of bone marrow involvement, but can be due to inflammatory changes.

International audience; The management of patients with chronic lymphocytic leukaemia (CLL) has improved with the utilisation of ofatumumab as a novel anti-CD20 monoclonal antibody. However, as half of the patients fail to respond to the treatment, the aim of this study was to evaluate circulating CLL cell depletion and clinical response according to the context of complement activation and FcγRIIIA polymorphism in ten CLL patients with relapsed/refractory disease. At the end of the treatment, results indicated that circulating CD5(+) CD19(+) CLL cell depletion was major (50% decrease) in 4 of 10 patients and ineffective for the two other patients. No clinical modifications were observed following ofatumumab introduction. Ofatumumab administration leads to a rapid and important exhaustion of complement C4 levels in patients with initial lymphocytosis. C4 exhaustion was accelerated in a non-responder patient, and incomplete in two patients with partial circulating depletion. Moreover, delaying weekly to monthly ofatumumab injections improved CLL cell depletion in two patients. FcγRIIIA 158 polymorphism (FF n = 6 and VF n = 4) was not associated with major and/or partial circulating CLL cell depletion. In conclusion, ofatumumab induces an important C4 exhaustion that needs to be taken into account when treating CLL patients with ofatumumab.

Rituximab is a chimeric human/mouse monoclonal antibody directed against the CD20 antigen. It has become part of the standard therapy for non-Hodgkin’s lymphoma (NHL). Rituximab effectively kills lymphoma B cells and rapidly leads to the sustained depletion of peripheral blood B cells. Mantle cell lymphoma (MCL) is incurable with standard therapy. The median survival time is short (43 months). Rituximab has been shown to trigger a response in between 20 and 38% of patients with MCL [1]. Sustained rituximab-induced B-cell depletion may compromise the immune system. Accordingly, some viral infections have already been reported in patients with NHL receiving chemotherapy in conjunction with rituximab. Here, we describe an unusual case of cytomegalovirus reactivation in one patient with MCL who had previously been treated with chemotherapy plus rituximab. A57-year-oldmanwasdiagnosedwithcyclinD1-positive inguinal bilateral MCL, Ann Arbor stage II, in March 2003. Before the start of chemotherapy, gammaglobulinemia was normal (10 g/l). He was treated with VAD (vincristine 0.4 mg/day on days 1–4, doxorubicin 9 mg/m/day on days 1–4, dexamethasone 40 mg/day on days 1–4) plus chlorambucil (6 mg/day on days 20–29) and rituximab (375 mg/m on day 28) (5 cycles) for 6 months. This chemotherapy corresponds to the GroupeOuest Est d’etude des Leucemies et Autres Maladies du Sang (GOELAMS) MCL 2001 clinical research protocol, which includes six cycles of VAD– chlorambucil–rituximab followed by therapeutic intensification with total-body irradiation (TBI) plus busulfan before autologous peripheral stem cell reinjection. Before the beginning of the treatment, hypercellularity associated with elevated protein levels in cerebrospinal fluid (CSF) let us suppose neuromeningeal localisation. Thus, intrathecal infusions (nine cycles) with methylprednisolone (40 mg), cytarabine (40mg) and methotrexate (15 mg) were administered. In October 2003, he was referred for accentuated neuromuscular weakness and diffuse chest pain associated with a persistent headache (10 days) resistant to usual painkillers. Clinical examination revealed neurological deficit affecting the psoas territory and the foot and finger elevators. Osteotendinous reflexeswere abolished.Nopulmonary, cardiac or abdominal manifestations were observed. Whole-body computed tomography (CT) found an interstitial syndrome without adenopathy. Electromyography and nerve conduction analysis did not find any acute signs but revealed chronic anterior horn cell lesions. Bone marrow aspirate was normal. Peripheral blood contained atypical basophilic lymphocytes, suggestive of lymphocyte activation. C-reactive protein concentration was moderately elevated (33 g/l). Hypogammaglobulinemia (5 g/l) without monoclonal secretion was found. Blood and bone marrow were negative for cyclin D1. Fluorescent in situ hybridisation (FISH) analysis failed to detect t(11;14) translocation in the CSF. Hepatic and kidney functions were normal. Blood cultures were negative for bacteria. Serum was positive for cytomegalovirus (CMV) IgG with a high avidity, showing prior immunity. Electroencephalography (EEG) showed a focal lesion in the frontal and temporal regions, but no associated clinical phenotype was observed. CSF contained an abnormally high amount of protein (0.63 g/l) and normal glucose and chloride levels. The CSF contained 38 leukocytes/mm (65% lymphocytes, 9% monocytes and 25% polynuclear S. Vallet (*) . A. Tran . M. C. Legrand-Quillien . V. Narbonne Department of Microbiology (E.A. Biodiversity and Microbial Ecology no. 3882), University Hospital Morvan, 2 avenue Foch, 29609 Brest Cedex, France e-mail: sophie.vallet@chu-brest.fr Tel.: +33-2-98223308 Fax: +33-2-98223987

Background The shared knowledge regarding management and outcome of PCNSL patients are usually based on results of clinical phase II studies that include limited series of selected patients, which imperfectly reflect the medical care in "real life". Methods The LOC network, certified by the national cancer institute (INCa), is a national network of expert centres for PCNSL. Since 2011, we are prospectively recording in the LOC database all newly diagnosed PCNSL patients from the 22 regional expert centres for PCNSL that cover the whole country. Data from PCNSL patients registered in the LOC database from January 2011 to March 18, 2016 were analyzed. Results Data from 971 patients were available in the LOC database at the time of analysis: sex ratio: 1.05, median age: 67 (18-92), median Karnofsky Performance Status: 60 (20-100), diffuse large B cell lymphoma: 97%, ocular involvement: 20%, cerebrospinal (CSF) involvement: 18%. Diagnosis procedure was biopsy (80%), tumor resection (9%), vitrectomy (8%), CSF cytology (3%). Treatment was initiated either by a neuro-oncology or a haematology team in 38% and 62%, respectively. Median delay between first symptoms and onset of treatment was 62 days. First line treatment was high-dose (HD) methotrexate (MTX) based chemotherapy (CT) (90%), other chemotherapy regimen (6%), or palliative care (4%). The use of Rituximab has gradually increased from 50 % of patients between 2011 and 2013, up to 87 % of patients in 2016. 16 % of patients were included in prospective trials. After first-line induction chemotherapy, responder patients < 60 years received a consolidation treatment in 75 % of cases consisting of either whole brain radiotherapy (WBRT) (49 %) or HD CT with autologous stem cell transplantation (HD CT-ASCT) (26 %). Low dose WBRT (23,4) is being used in younger CR patients since 2014. In responder patients > 60 years, WBRT was seldom given (9%) according to national guideline, and HD CT-ASCT was offered to 1% of patients. Response rates to first-line treatment among evaluable patients (n = 655) were: complete response: 59%; partial response: 10%; stable disease: 3%; progressive disease: 28%. Relapse occurred in 42 % patients < 60 y and in 62 % in older patients. At relapse, second line chemotherapy, HD CT-ASCT, WBRT and palliative care were offered in 50%, 18%, 12%, 20% of patients respectively. With a median follow-up of 20.4 months, median progression free survival (PFS) was 9.9 months for the whole population (< 60 years: 34.6 months; > 60 years: 7.9 months). Median overall survival (OS) and 5-year OS were 30 months and 41% respectively (< 60 years: not reached, 68%; > 60 years: 15 months, 30%). Conclusion The therapeutic practices in France reflect the current knowledge and controversies in PCNSL. Long-term survival has become frequent, especially among youngest patients who usually receive a consolidation treatment and to whom HD CT-ASCT can be offered at relapse. Relapse rate remains frequent and especially in elderly patients in whom consolidation treatment is omitted. Such an overview points out a couple of issues. Despite homogeneous treatments following national guidelines in accordance with the state of the art of medical care, standards of care are to be challenged, both for increasing the CR and decrease the relapse rates. The development of target and innovative therapies in PCNSL alone or in combinatorial regimen is needed. PFS and OS of patients according to age Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Soussain: Roche: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding. Ghesquieres:Mundipharma: Consultancy; Roche France: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Choquet:Janssen: Consultancy; Celgene: Consultancy. Morschhauser:Servier: Consultancy, Honoraria; Janssen: Honoraria; Gilead Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria.

Unavailability of Carmustine and its dramatically increased cost by nearly 10 fold has led to its replacement by bendamustine (Be) and an increase use of Bendamustine-based (BeEAM) conditioning regimen before autologous stem cell transplantation for lymphoma. The aim of this study was to evaluate the safety of the BeEAM regimen in the real life use in several French centers. Median age of the 386 patients (233 male, 153 female) was 55 years (17-72). The majority of patients had aggressive B-cell (40%), follicular (17%), Hodgkin's (17%) and mantle cell lymphoma (15%). Two hundred and forty six patients (64%) were transplanted after 2nd line chemotherapy and the median number of prior lines of chemotherapy of 2 (1-9). Two hundred and sixty patients (67%) had received prior platinum chemotherapy and only 4% had a history of prior chronic renal failure (Table 1). The median creatinine level at conditioning initiation was 71(36-206) µmol/l. Be was administered at a median dose of 191 mg/m2/day (50-250) on day -7 and -6. Thirty two percent received 100-160 mg/m²/d and 58% of patients received more than 160 mg/m²/d. Median 24h-hydration volume was 3 l (1-6) which began within median time of 18 h (1-72) prior to conditioning initiation. The median duration time of Be perfusion was 60 min (30-143). Grade 1-4 acute renal failure (ARF) was reported in 107 cases (28%) (G ≥2; 34%) and appeared after a median time of 2 days (1-18) after conditioning start. Melphalan dosage was reduced, due to renal failure, in 10% of patients (Table 2). 84% of patients normalized their creatinine level within a median time of 10 days (1-77). The most frequent reported Grade 1-4 toxicities were mucositis (84%), gastroenteritis (53%), skin toxicity (34%), colitis (29%), liver toxicity (19%), pneumonitis (5%) and cardiac rhythm disorders (4%). Opportunistic infection was documented in 9.5% of patients, HHV6 reactivation in 6% of patients. Ten percent of patients needed intensive care management and toxic death was estimated at 5% (Table 3). Patients received a median of 3 (0-34) packed red blood cells and 4 (0-56) platelets units. The median time to neutrophils > 0.5 G/L and platelets > 20 G/L were 10 (0-50) and 12 (0-210) days. The median time of hospital stay was 23 (12-85) days. In comparison with the group of patient without renal failure, the group of patients with ARF had older age (58 vs 54), higher rate of pre-transplant chronic renal failure (10% vs 1%), higher rate of platinum treatment (77% vs 64%), higher day1 creatinine level (81 vs 69) and received higher median bendamustine (199 vs 182). Colitis (p=0.039), pneumonitis (p=0.008), cardia arrhythmia (p=160mg/m2 and age were independent prognostic factors for ARF. A three-point clinical predictor score for acute renal failure was identified and included creatinine level>65µmol/l, bendamustine dose >160mg/m² and age>57 years. ARF stratified by score, was 4% with score 0, 17% with score 1, 30% with score 2 and 45% with score 3. In conclusion, BeEAM induced 5% non-relapse mortality with high rate of renal toxicity. A simple, three-point scoring system can stratify patients by levels of risk for ARF. Rapid identification of higher risk patients may allow a reduction of the bendamustine dose to improve clinical outcomes. Prospective comparative studies are needed to confirm toxicity extents of this conditioning as compared with other type of high dose therapy. Disclosures Soussain: Pharmacyclics: Research Funding; Celgene: Research Funding; Roche: Research Funding. Malak:Novartis: Membership on an entity's Board of Directors or advisory committees.

Background The proliferation index (PI), defined by KI67 protein expression has been identified as a key prognostic factor (PF) in mantle cell lymphoma (MCL) (1, 2). A GOELAMS/LYSA study (n = 113 patients) identified a cut point of 26% for KI67 positivity as an independent predictor of overall survival together with LDH levels, B symptoms and ECOG-PS, in MCL (GOELAMS index : GI). (1) Recently, the European MCL network confirmed the independent prognostic power of KI67 protein expression levels to predict OS in MCL (n = 508) and proposed a new score "MIPIc" (KI67cut-off of 30%). (2) While these scores show prognostic impact in the immuno-chemotherapy setting, with or without ASCT and / or maintenance therapy, their predictive power in the setting of targeted therapy remains uncertain. Objective The aim of this study was to test the predictive power of the MIPIc and GI prognostic indices in a cohort of elderly MCL patients treated by a proteasome-inhibitor-based immunochermotherapy regimen within a prospective phase II trial of the LYSA group (LyMa SA 2010 ; Rituximab, Bendamustine, Velcade and Dexamethasone regimen : RiBVD). (3) Material and method The final analysis of the LyMA SA 2010, presented at ASH 2014 (3), showed overall clinical and molecular response rates of 86.5% and 85%. The 24 months estimated OS and PFS was respectively 80% and 70%. (3) In order to assess the prognostic power of KI67 expression levels for OS, all survival data were updated. KI67 staining was performed and reviewed centrally by one pathologist of the LYSA-P, according to the European guidelines. (4) The MIPIc and GI scores were calculated and their impact on survival analyzed (Logrank). In addition, all 6 variables comprising the MIPc and the GI indices were assessed separately by univariate analyzes for prognostic value (these were LDH, ECOG and KI67 that are common to the 2 indices, and Age and WBC for the MIPIc and B Symptoms for GI). Finally a Logrank permitted to define 3 groups of patients with a high statistically impact on survivals with the 3 common variables of MIPIc and GI. Results Among the 74 elderly MCL patients treated in first line by the RiBVD regimen, 59 are alive with a median follow up of 40 months. Estimated OS and PFS at 36 months are respectively 78.4% and 65%. The MIB1 was evaluated on 58 samples for which the MIPIc and GI could be calculated for 57 patients (no LDH value for one patient). MIPIc and GI were not able to define relevant prognostic subgroups for OS (p =0.55 and 0.11). Only the 3 common variables LDH (N vs >N), ECOG (O-1 vs >1) and MIB1 (with a cut-off at 46% corresponding to the fourth quartile of MIB1 expression levels) were individually predictive of OS by univariate analysis (respectively with p=0.0006, p=0.048 and p=0.0031). With these three variables the Logrank test separated three groups that were statistically discriminant for OS and PFS: one group with 0 risk factors n=24 patients, 42%), a second group with one risk factor (n=20 patients, 32%) and the last group with 2 or 3 risk factors (n=13 patients, 23%). Hence the 3 year OS of these 3 groups was respectively 96%, 75% and 30% (p In Conclusion The proteasome-inhibitor-based immunochemotherapy regimen, RiBVD, induces prolonged survival of "High risk" patients, as defined by this modified MIPIc score. More proliferative disease, defined by a KI67 superior to 46%, combined with a high LDH level and/or a high PS defines a high subgroup of patients under the RiBVD regimen (median PFS and OS of respectively 15 and 10 months). Ref: 1 Gressin R, Haematologica 2010. 2 Hoster E et al, J Clin Oncol 2016. 3 Gressin R et al, ASH Blood 2014. 4 Klapper W, H Hematop 2009. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Cartron: Roche: Consultancy, Honoraria; Celgene: Honoraria; Gilead: Honoraria; Jansen: Honoraria. Dartigeas:Roche: Consultancy; Mundipharma: Other: travel grant. Dupuis:janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Karlin:takeda: Consultancy; Bristol: Consultancy; celgene: Consultancy, Honoraria; janssen-cilag: Consultancy, Honoraria; amgen: Consultancy, Honoraria.

Introduction Post-transplant lymphoproliferative disorders (PTLD) are a rare but severe complication occurring after organ transplantation as a result of immunosuppressive therapy (IST). Until recently, there was no consensus regarding best treatment practice. In 2006, a phase 2 trial using a monotherapy with rituximab showed an overall response rate of 44%, with a complete response (CR) rate of 28%. In 2012, the PTLD-1 international multicenter trial evaluating rituximab followed by CHOP chemotherapy proved an efficacy of 90% and an overall survival of 6.6 years in PTLD treatment. K-virogref is a French national expert network created in 2011 to structure and improve the management of viro-induced cancers, occurring in adult after transplantation, including PTLD. Within this network, an epidemiological observational study has been set up in September 2013. The aim of our study was to analyze the management of PTLD in France before the creation of the national database of K-virogref. Patients and methods We included solid organ or allogeneic stem cell recipients, aged 18 years and above, with a histologically proven PTLD, diagnosed between January 2010 and September 2013 in 19 French hematology departments. We collected from clinical charts data regarding transplant characteristics, PTLD presentation, first-line treatment and outcomes. Results The study population consisted of 94 patients, 67% were men and median age was 53 years (ranging 18 - 81 years). The majority of patients received kidney transplantation (54%), followed in almost equal proportion by heart (13%), liver (13%) and allogeneic stem cell transplantation (10%). Most of the time (80% of patients), PTLD occurred more than one year after organ transplantation with a median delay of 7.8 years. Histologically, mainly monomorphic PTLD were observed with 66% of diffuse large B cell lymphoma and PTLD was EBV associated in 54%. At the time of diagnosis, 80% were classified as stage IV according to Ann Arbor. The median follow-up time was 28.3 months (ranging 0.2 - 78 months). As far as treatment is concerned, modification of IST was performed in 68% of patients but response was rarely evaluable because a specific treatment was often started at the same time. Surprisingly, first line treatment consisted in rituximab alone or rituximab followed by CHOP chemotherapy in only 32% of the patients. Among these patients, the overall response rate was 81% with 55% of CR. Most patients (56%) received chemotherapy (n=11) or immunochemotherapy (n=46) without previous rituximab therapy. For these patients the overall response rate was 71% with a CR rate of 53%. At 1 and 3 years of follow-up, the relapse-free rates were 56% (95% confidence interval (CI) 46% - 68%) and 47% (95% CI 37% - 60%), respectively. Overall, 49% of patients died during follow-up of which 37% due to infectious complications and 32% due to PTLD progression. Conclusion This is one of the largest cohort study of PTLD in the literature, providing an overview of epidemiological features, treatments and outcomes of this rare disease. The lag between the management of PTLD and literature data emphasizes the usefulness of a national expert network such as K-virogref in order to generalize a less toxic and more powerful attitude. Disclosures Leblond: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Choquet:Celgene: Consultancy; Janssen: Consultancy.

Dear Editor,Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin ’s lymphoma that is characterized by a typicalcytological presentation, the presence of the t(11;14)(q13;q32) chromosomal translocation, and overexpression ofcyclin D1. MCL has a low response rate and shortprogression-free survival (PFS) after conventional therapy.In refractory or relapsed MCL, the prognosis is even worse.Several novel therapeutic approaches have been proposed,including monoclonal antibodies, radioimmunotherapy,proteasome inhibitors, m-TOR inhibitors, and the immuno-modulatory drugs thalidomide and lenalidomide. In ourpatient with refractory MCL, the use of lenalidomide assingle agent therapy allowed for complete cytological,phenotypic, and cytogenetic remission in a very shortperiod of time.A 74-year-old woman was first seen for asthenia and thepresence of abnormally circulating B lymphocytes. Theclinical examination only identified grade I splenomegaly.The blood count revealed lymphocytosis at 8.96 Giga/L with30% circulating lymphocytes, which presented with thetypical MCL phenotype, CD5

Background: Many patient (pt) and disease factors have been shown to impact prognosis in multiple myeloma (MM). A recently described frailty scale categorized pts with MM into 3 groups: fit, intermediate, and frail based on age, comorbidities, and physical and cognitive functioning (Palumbo, Blood, 2015). These groups were predictive of risk of death. The pivotal phase 3 FIRST trial examined the impact of continuous therapy with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) on outcomes in transplant-ineligible pts with newly diagnosed MM (NDMM; Benboubker, N Engl J Med, 2014). In this study, Rd continuous resulted in progression-free survival (PFS) and overall survival (OS) benefits compared with melphalan-prednisone-thalidomide (MPT). This analysis examined outcomes in pts by severity of frailty score in the FIRST trial, the largest clinical trial of transplant-ineligible NDMM to date. Methods: Pts with NDMM who were ineligible for transplant were randomized to treatment with Rd continuous, Rd for 18 cycles (Rd18; 72 weeks), or MPT for 12 cycles (72 weeks). Pts were categorized into 3 severity groups using a score based on age, Charlson Comorbidity Index score, and the Activities of Daily Living (measures of self-care) and Instrumental Activities of Daily Living (measures of usual activities) scales from the EQ-5D questionnaire at baseline, as previously described (Palumbo, Blood, 2015). This analysis examined PFS and OS outcomes by severity group in the overall pt population and between the Rd continuous and MPT arms, which were the primary comparators in this study, using an updated data cutoff of March 3, 2014. Results: This analysis included 1517 of 1623 pts from the intent-to-treat population; 106 pts were excluded because they did not have the required baseline data from the EQ-5D. The majority of pts enrolled in the FIRST trial were frail (54%) compared with fit (17%) or intermediate (30%). Similar breakdowns were observed across treatment arms (Figure 1). Frail pts were older and had higher Eastern Cooperative Oncology Group performance status scores, higher International Staging System (ISS) stage, higher lactate dehydrogenase levels, and worse renal function than fit or intermediate pts. In the overall pt population, better fitness was associated with significantly improved OS compared with worse fitness: fit vs intermediate (hazard ratio [HR] = 0.66; P = .004), fit vs frail (HR = 0.42; P < .0001), intermediate vs frail (HR = 0.62; P < .0001). Rd continuous treatment prolonged PFS compared with MPT for all pt severity groups (Figure 2). Rd continuous reduced the risk of progression or death vs MPT by 44%, 38%, and 21% in fit, intermediate, and frail groups, respectively. OS was also extended with Rd continuous vs MPT for all pt severity groups (Figure 2). Risk of death was reduced by 48%, 28%, and 20% in the fit, intermediate, and frail groups, respectively, with Rd continuous compared with MPT. Causes of death were primarily MM or complications of MM in fit (62% of deaths) and intermediate (57% of deaths) pts; while they were the cause of death in half of frail pts. Pts were further categorized within each fitness group by ISS stage: fit pts were classified by stage I vs II/III and intermediate and frail pts were classified by stage I/II vs III. Addition of ISS stage further improved prognostic classification within each severity group for both PFS and OS. Discussion: Results validated the feasibility of using the frailty scale for predicting risk of death in pts with NDMM and further demonstrated an association with PFS outcomes. The majority of pts fell into the frail category, which was associated with the poorest outcomes, indicating a need to further improve outcomes for a large proportion of pts with MM. Rd continuous resulted in PFS and OS benefits compared with MPT regardless of severity of frailty level, with the greatest benefits observed in fit pts. Poor outcomes of frail pts are likely further impacted by a higher proportion of deaths due to causes independent of MM compared with fit and intermediate pts, such as pre-existing comorbidities. These data support the use of Rd continuous as a standard frontline treatment option, even for frail pts with NDMM who are older and may have comorbidities or physical or cognitive impairments. Figure 1. Breakdown of Severity Group by Treatment Arm Figure 1. Breakdown of Severity Group by Treatment Arm Figure 2. PFS and OS by Pt Severity Group Figure 2. PFS and OS by Pt Severity Group Disclosures Facon: Celgene: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Hulin:Celgene Corporation: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Dimopoulos:Janssen-Cilag: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Mohty:Celgene Corporation: Honoraria, Research Funding. Zamagni:Celgene Corporation: Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Renwick:Amgen: Other: Travel; Bayer: Speakers Bureau. Tempescul:Gilead: Other: Export Board Committee. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria. Sturniolo:Celgene Corporation: Employment. Ervin-Haynes:Celgene Corporation: Employment.

Introduction Le prurit aquagenique (PA) est une sensation intense de picotements apres un contact avec l’eau. C’est le symptome le plus handicapant decrit par les patients atteints de polyglobulie Vaquez (PV). Un prurit est egalement decrit dans les 2 autres neoplasies myeloproliferatives (NMP) : la thrombocytemie essentielle (TE) et la myelofibrose (MF) sans toutefois preciser s’il s’agit de PA ou non. Materiel et methodes Nous avons mene une etude prospective (questionnaire) sur 70 patients pris en charge pour NMP (43 PV, 15 TE et 12 MF) ayant declares souffrir de PA a un moment donne de leur maladie. L’objectif principal de cette etude etait de decrire les circonstances de survenue, de duree et les caracteristiques du prurit, ainsi que l’influence des traitements cytoreducteurs recus. Le deuxieme objectif etait de determiner s’il existe un seul PA commun a tous les NMP ou plusieurs types de PA, ceci en fonction des NMP. Observations Le premier resultat de cette etude etait que les patients ayant une TE ou une MF decrivaient egalement un PA. Resultats Comparativement, les patients PV etaient plus nombreux a decrire la survenue du PA avant le diagnostic de leur hemopathie (p Discussion En resume, cette etude montre que le PA n’est pas un symptome exclusif a la PV mais peut aussi etre un symptome de MF ou de TE. Certaines differences cliniques entre les sous-types de NMP ont ete mises en evidence. Conclusion Le PA est donc present dans les tous les NMP. Une analyse clinico-biologique plus poussee permettra de mieux comprendre sa physiopathologie et d’envisager de nouveaux traitements du PA.

4879 Background: In Waldenstrom9s Macroglobulinemia (WM), response rates to rituximab (RTX) range from 30% to 75%. RTX is also known to generate a transient IgM flare in some patients. Our study aimed to characterize this phenomenon using the newly Hevylite® assay developed by The Binding Site that specifically quantifies IgM-kappa(K) and IgM-lambda(L). Methods: Between 2007 and 2009, 33 WM patients received a 6-course fludarabine-based regimen, 32 as first and 1 as second line. Partial response (PR), defined as a reduction ≥50% but Results: Of the 33 tested, at a variation threshold ≥20% relative to baseline IgM levels, 3 subgroups were defined: 15 or 45.5%, the no-flare patients, showed an increase or a decrease vs 1 L ( p p p =0.22). We also analyzed the data without defining a critical threshold in monoclonal IgM level variations. Patients were, then, separated in 2 subgroups: 17 flare patients and 16 anti-flare patients. Monoclonal K light chain was overrepresented in the 2 subgroups, with 13 K vs 4 L in flare patients and 13 K vs 3 L in anti-flare patients; no statistically significant difference was found between them regarding monoclonal K and L light chains ( p =0.32). No association was seen with demographic and hematologic characteristics and RTX pharmacokinetics. Regarding FcgR IIIa-158 polymorphism, there was a statistically significant difference ( p =0.03) as 12 patients were of the FF subtype and 5 of the VF one in the flare subgroup while 4 were of the FF subtype, 11 of the VF one and 1 of the VV one in the anti-flare subgroup. At response evaluation 3 months after the fourth injection of RTX, all patients were screened for SPE and 22 for IF. When we compared the 17 patients of the flare subgroup to the 16 ones of the anti-flare subgroup, no patient vs 1 reached complete remission defined as disappearance of BMP on SPE and negativity of IF, 1 vs 6 advanced to very good partial response defined as a decrease ≥90% in BMP on SPE and positivity of IF and the remaining 16 vs 9 improved their partial response by a mean additional reduction of 20% (range: 0–30%) vs 18.75% (range: 0–50%) in BMP, but there was no statistically significant difference in this regard ( p =0.79). Conclusions: Using Hevylite® assay, monoclonal IgM up and down variations of at least 20% following RTX occurred in up to 54.5% of our patients and this raised to 100% when no threshold value was considered. Such assay provides a reliable and highly sensitive quantitative assessment, especially in patients whose monoclonal IgM was at low concentration. Patients of the flare subgroup were predominantly of the FF subtype of FcgR IIIa-158 polymorphism while patients of the anti-flare subgroup were predominantly of VF subtype, which was statistically significant. It is tempting to hypothesize a difference in RTX mechanism of action, with ADCC predominating in the anti-flare subgroup and CDC in the flare subgroup. It would be of interest to assess such an hypothesis on a larger cohort and to analyze its impact on response profile. Disclosures: Pietrantuono: The Binding Site: Employment.

e170 with CD 34+ counts < 15/ml required a second day of leukapheresis. Median CD 34+ cells collected on Day 5 were 2.01 x 10/kg (0.67-8.04). Median total CD34+ cells collected were 3.55 x 10/kg (1.1811.75). Median days to neutrophil and platelet engraftment were 10 days (9-16 days) and 12 days (7-36 days) respectively. Conclusion: Day 4 stem cell collection is feasible and potentially cost effective in a majority of myeloma patients. A CD 34+ count of

We report here two cases of patients with acute myeloblastic leukemia, type M1 (FAB classification), associated with a t(10;17)(p15;q21). Fluorescence in situ hybridization with the LSI PML/RARA dual-color probe showed the breakpoint to be distal to the RARA locus. Four other patients with this translocation have been reported, three of them having acute undifferentiated or poorly differentiated leukemia.