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Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event-free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1-3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re-treatment, or death due to any cause. OS was compared to age-and-sex-matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78-4.88; Lyon SMR = 8.74, 95%CI: 5.41-13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56-0.94, Lyon SMR = 1.02, 95%CI: 0.58-1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97-25.02, Lyon SMR = 19.10, 95%CI:9.86-33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31-17.74, Lyon SMR = 7.22, 95%CI:4.13-11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096-1101, 2016. © 2016 Wiley Periodicals, Inc.

BACKGROUND Altered Toll-like receptor (TLR) expression levels and/or mutations in its signaling pathway (such as MyD88 mutation) contribute to the pathogenesis of lymphoproliferative disorders (LPD). CD180 is an orphan member of the TLR family that modulates the signaling of several TLRs, but only limited studies have evaluated its expression by flow cytometry (FCM) in LPD. METHODS Using a multiparameter FCM approach, we have assessed CD180 mean fluorescence intensity (MFI) in lymph nodes (LNs) and peripheral blood (PB) samples obtained from patients with follicular lymphoma (FL; LN/PB, n = 44/n = 15), chronic lymphocytic leukemia (CLL, n = 26/n = 21), mantle cell lymphoma (MCL, n = 13/n = 17), and marginal zone lymphoma (MZL, n = 16/n = 12). Specimens from non-tumoral PB and LN (n = 8/n = 12) were used as controls. RESULTS In the LN specimens, FL and control B-cells showed similar CD180 expression (MFI = 1,049 vs. 1,381, P > 0.05; Mann-Whitney U-test). This level was markedly lower in the other LPDs, MCL (MFI = 396, P 0.05). However, the CD180 expression of FL B-cells assessed in PB was dim and/or negative, in the same range as MCL and CLL (FL MFI = 453, MCL MFI = 305, CLL MFI = 420, P > 0.05) but lower than in MZL (MFI = 895, P

Purpose Although the life expectancy of patients with follicular lymphoma (FL) has increased, little is known of their causes of death (CODs) in the rituximab era. Patients and Methods We pooled two cohorts of newly diagnosed patients with FL grade 1-3A. Patients were enrolled between 2001 and 2013 in two French referral institutions (N = 734; median follow-up 89 months) and 2002 and 2012 in the University of Iowa and Mayo Clinic Specialized Program of Research Excellence (SPORE; N = 920; median follow-up 84 months). COD was classified as being a result of lymphoma, other malignancy, treatment related, or all other causes. Results Ten-year overall survival was comparable in the French (80%) and US (77%) cohorts. We were able to classify COD in 248 (88%) of 283 decedents. In the overall cohort, lymphoma was the most common COD, with a cumulative incidence of 10.3% at 10 years, followed by treatment-related mortality (3.0%), other malignancy (2.9%), other causes (2.2%), and unknown (3.0%). The 10-year cumulative incidence of death as a result of lymphoma or treatment was higher than death as a result of all other causes for each age group (including patients ≥ 70 years of age at diagnosis [25.4% v 16.6%]) Follicular Lymphoma International Prognostic Index score 3 to 5 (27.4% v 5.2%), but not Follicular Lymphoma International Prognostic Index score 0 to 1 (4.0% v 3.7%); for patients who failed to achieve event-free survival within 24 months from diagnosis (36.1% v 7.0%), but not for patients who achieved event-free survival within 24 months of diagnosis (6.7% v 5.7%); and for patients with a history of transformed FL (45.9% v 4.7%), but not among patients without (8.1% v 6.2%). Overall, 77 of 140 deaths as a result of lymphoma occurred in patients whose FL transformed after diagnosis. Conclusion Despite the improvement in overall survival in patients with FL in the rituximab era, their leading COD remains lymphoma, especially after disease transformation. Treatment-related mortality also represents a concern, which supports the need for less-toxic therapies.

International audience; Over recent years, there has been increasing interest in the use of the anelloviruses, the major component of the human virome, for the prediction of post-transplant complications such as severe infections. Due to an important diversity, the comprehensive characterization of this viral family over time has been poorly studied. To overcome this challenge, we used a metagenomic next-generation sequencing (mNGS) approach with the aim of determining the individual anellovirus profile of autologous stem cell transplant (ASCT) patients. We conducted a prospective pilot study on a homogeneous patient cohort regarding the chemotherapy regimens that included 10 ASCT recipients. A validated viral mNGS workflow was used on 108 plasma samples collected at 11 time points from diagnosis to 90 days post-transplantation. A complex interindividual variability in terms of abundance and composition was noticed. In particular, a strong sex effect was found and confirmed using quantitative PCR targeting torque teno virus, the most abundant anellovirus. Interestingly, an important turnover in the anellovirus composition was observed during the course of the disease revealing a strong intra-individual variability. Although more studies are needed to better understand anellovirus dynamics, these findings are of prime importance for their future use as biomarkers of immune competence.

TO THE EDITOR: Peripheral T-cell lymphomas (PTCLs) are heterogeneous diseases resulting from the malignant transformation of mature T or natural killer cells. Their epidemiology varies widely, but PTCLs that derive from T follicular helper (TFH) cells, which include angioimmunoblastic T-cell

Diffuse large B cell lymphoma represents the most common type of non-Hodgkin lymphoma. Although the curability rate is high, around 40% of patients will relapse or exhibit refractory disease. To obtain long-term disease-free survival after relapse, an intensive salvage regimen followed by autologous steam cell transplant remains the standard of care. However, more than 60% of patients will be transplant ineligible, presenting a therapeutic challenge. In this setting, there is no definitive standard approach, as management should be individualized according to patient tolerance. Importantly, these transplant ineligible patients are ideal for consideration of novel agents. In this review, we will discuss the incidence, outcome, and management of relapsed and refractory DLBCL, as well as explore some of the novel agents in development.

Summary Background Histological transformation of follicular lymphoma to aggressive lymphoma is a serious event with a substantial effect on patient outcome. The aim of the Aristotle study was to assess the effect of rituximab on the risk of histological transformation and its outcome. Methods 11 cooperative groups or institutions across Europe contributed data to this study. Eligible patients (≥18 years) had histologically confirmed follicular lymphoma grade 1, 2, or 3a, diagnosed between Jan 2, 1997, and Dec 20, 2013. Histological transformation was defined as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy. The primary endpoints were the cumulative hazard of histological transformation and survival after transformation. Findings Information was available for 10 001 patients with follicular lymphoma, 8116 of whom were eligible for analysis. 509 histological transformations were reported. After a median follow-up of 87 months (range 1–221; 2·5–97·5th percentile 5–160), the 10-year cumulative hazard of histological transformation was 7·7% (95% CI 6·9–8·5). The 10-year cumulative hazard of histological transformation was 5·2% (95% CI 4·5–6·2) in patients who received rituximab and 8·7% (7·2–10·6) in those who did not (hazard ratio [HR] 0·73, 95% CI 0·58–0·90; p=0·004). The 10-year cumulative hazard of histological transformation was 5·9% (95% CI 5·0–7·0) for patients who received induction rituximab only and 3·6% (95% CI 2·3–5·5) for those treated with induction and maintenance rituximab (HR 0·55, 95% CI 0·37–0·81; p=0·003). This finding was confirmed in a multivariate analysis (p=0·016). 287 deaths were recorded in 509 patients with histological transformation, resulting in a 10-year survival after transformation of 32% (95% CI 26–38). Survival after transformation did not differ between patients not exposed to rituximab and those who received rituximab in induction only (HR 0·94, 95% CI 0·69–1·28; p=0·70), and those who received rituximab in induction and maintenance (0·96, 0·58–1·61; p=0·88). Interpretation The risk of histological transformation as a first event can be significantly reduced by the use of rituximab. These findings support the need to inform patients using rituximab nowadays that the risk of transformation is lower than it was before the introduction of rituxumab. Funding Associazione Angela Serra per la Ricerca sul Cancro, European Lymphoma Institute, European Hematology Association Lymphoma Group, Fondazione Italiana Linfomi, Spanish Group of Lymphoma and Bone Marrow Transplantation.

National audience

International audience; Optimal salvage chemotherapy regimen for patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma remains unclear but often based on platinum regimens. This retrospective study assesses in real life the toxicities profiles of patients with relapsed or refractory lymphoma treated with DHA (dexamethasone, high dose aracytine cytarabine) plus platinum salt (dexamethasone-High dose aracytine (cis)platin (DHAP), dexamethasone-High dose aracytine carboplatin (DHAC), or dexamethasone-High dose aracytine Oxaliplatin (DHAOX)), from February 2007 to May 2013 in 2 French hospitals. Toxicities were recorded from medical files and assessed according to the National Cancer Institute Common Toxicity Criteria version 3.0. Potential risk factors of renal insufficiency were tested by univariate analyses. A total of 276 patients were treated: 168 with DHAP (60.9%), 79 with DHAOX (28.6%), and 29 with DHAC (10.5%). Rituximab was associated in 80.1% of patients (n = 221). Renal failure was reported in 97 patients, mainly with cisplatin regimen (86.6%) leading to 8.9% grade III to IV renal failure (P = .001). Renal insufficiency was reversible in most patients but remained persistent in 24, with all of them being treated with DHAP except 1. Cisplatin-based regimen (50.0% versus 12.0%, P \\textless .05) and female (44.6% versus 29.7%, P \\textless .05) appeared to be at higher risks of renal failure. Platinum cumulative dose is a significant risk factor of nephrotoxicity. Hematologic toxicity was more frequent with carboplatin and cisplatin with at least 1 event (all toxicity grade) respectively in 79.3% and 71.4% of patients treated (P \\textless .005). Auditory toxicity was mainly reported with cisplatin (n = 19; 4 grade I-II and 15 grade III-IV). Oxaliplatin was implicated in 77.6% of neurotoxicity (n = 59), mainly moderate (grade I-II). In conclusion, DHAOX and DHAC regimens have more favorable toxicity profile than DHAP regimen. Their lack of renal toxicity makes them attractive regimens, which may be interesting for patients eligible for autologous stem cell transplantation. Nevertheless, these results have to be confirmed by the therapeutic efficacy of these 3 regimens

Gemtuzumab ozogamicin (fGO), a humanized anti-CD33 monoclonal antibody linked to calicheamicin in combination with intensive chemotherapy gives high response rates in adult acute myeloid leukemia (AML) patients in relapse. However, reduced intensity chemotherapy in combination with fractionated GO has not been tested in aged relapsing patients. Patients from our institution with CD33+ AML aged 55 years or more in first late relapse (≥ 6 months) were proposed participation in a GO compassionate use program. Induction therapy consisted in fractionated GO (fGO; 3 mg/m², days 1, 4, 7) with standard-dose cytarabine (200 mg/m² /day, 7 days). Patients were consolidated with two courses of GO and intermediate dose cytarabine. Twenty-four patients (median age 68 years) received fGO with cytarabine. Median follow-up was 42 months. The response rate was 75%, including complete remission (CR) in 16 patients and CR with incomplete platelet recovery (CRp) in two patients. Two-year overall survival (OS) was 51% (95% CI: 28-69) and 2 years relapse-free survival (RFS) was 51% (95%CI: 25-72). Duration of second CR (CR2) was longer than first CR (CR1) in 9 out of 18 patients. Minimal residual disease (MRD) was negative in evaluable patients in CR2, particularly in NPM1 mutated cases. Toxicity was in line with that of the same fractionated single agent GO schedule. Fractionated GO with low intensity chemotherapy produced high response rates and prolonged CR2 in aged AML patients in first late relapse.

In diffuse large B-cell lymphoma (DLBCL), the age-adjusted International Prognostic Index (aaIPI) score is currently used to predict patient outcomes and to choose the best therapeutic treatment. Body mass index (BMI) and gender are occasionally sited as prognostic factors; however, their value has never been studied in a large series of patients included in prospective clinical trials in the rituximab era. To assess the impact of BMI and gender on OS and PFS independently of the aaIPI score, we pooled 985 patients that were prospectively included in GELA studies and uniformly treated with R-CHOP. Univariate analysis indicated that high aaIPI and male gender were associated with a worse PFS, whereas high (>25) or low (

ADCC : antibody dependant cell-cytotoxicityAITL : lymphome T angio-immunoblastiqueALCL : lymphome anaplasiqueALK : anaplastic lymphoma kinaseATLL : adult T-cell leukemia/lymphomaBTK : Bruton tyrosine kinaseChl : chloraminopheneCSH : cellules souches hematopoietiquesCTLC : lymphome T cutaneDLBCL : lymphome diffus a grandes cellules BDXM : dexamethasoneEATL: enteropathy-associated T-cell lymphomaEBV : virus d’Epstein-BarrEFS : event free survival [survie sans evenement]GELF : [...]

International audience; Mediastinal gray zone lymphoma, B-cell lymphomas with intermediate features between classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, have not been well described in the literature. We report the clinical characteristics and outcomes of a large retrospective series of 99 cases centrally reviewed by a panel of hematopathologists, with a consensus established for the diagnosis. Cases were defined as classical Hodgkin lymphoma-like morphology (64.6%) with primary mediastinal B-cell lymphoma immunophenotype, primary mediastinal B-cell lymphoma-like morphology (30.3%) with classical Hodgkin lymphoma or composite (5.1%) (synchronous occurrence of classical Hodgkin lymphoma and primary mediastinal B-cell lym-phoma). The median age was 32 years (13-83 years); 55% were women. Thirteen of 81 evaluable cases (16%) were Epstein-Barr virus-positive. Twenty-eight percent of patients presented primary refractory disease (progression under first-line treatment or relapse within one year). The 3-year event-free and overall survival rates were 63% and 80%, respectively. Patients treated with a standard regimen (RCHOP/ABVD) had worse event-free survival (P=0.003) and overall survival (P=0.02) than those treated with a dose-intensive chemotherapy (high-dose RCHOP/escalat-ed BEACOPP). Rituximab added to chemotherapy was not associated with better event-free survival (P=0.55) or overall survival (P=0.88). Radiotherapy for patients in complete remission had no impact on event-free survival. In multivariate prognostic analysis, ECOG-PS and anemia were the strongest factors associated with a shorter event-free survival and overall survival, respectively. In conclusion, this report describes the largest series of mediastinal gray zone lymphoma. Our data suggest that a dose-intensive treatment might improve the outcome of this rare and aggressive disease.

Introduction: The recently developed DLBCL90 NanoString assay robustly distinguishes primary mediastinal large B-cell lymphoma (PMBCL) from diffuse large B-cell lymphoma (DLBCL), as well as cell-of-origin (COO) subtypes of DLBCL (ABC, GCB, unclassified) and cases with a Double-Hit (DHIT) signature (Ennishi D., JCO 2019). When this assay was applied to biopsies from 343 patients with de novo DLBCL uniformly treated with R-CHOP, nineteen of these cases had a molecular PMBCL signature (mPMBCL), despite the fact that they were diagnosed as DLBCL based on their morphology, immunophenotype and clinical features. Here, we aimed to comprehensively characterize the molecular and clinicopathologic features of these mPMBCL cases. Methods: Survival estimates were calculated using Kaplan-Meier analysis, using time to progression (TTP) and disease specific survival (DSS) as endpoints. We applied whole-exome sequencing, copy number analysis (SNP6.0) and RNAseq to identify somatic mutations, copy number aberrations and differentially expressed genes, respectively. FISH was applied to assess the presence of rearrangements affecting MYC, BCL2 and BCL6. We used data previously obtained within our centre from a PMBCL cohort (n=73) to compare mPMBCL with "bona fide" PMBCL (PMBCL) tumors (Mottok et al, Blood 2019). Results: Median age at diagnosis was significantly higher for mPMBCL compared to PMBCL (62 vs 37 years, p Comparison of the mutational landscape of mPMBCL to PMBCL demonstrated perturbations in the central hallmarks of PMBCL pathogenesis: JAK/STAT signaling, NF-ĸB pathway activation and immune evasion. Genomic aberrations affecting JAK-STAT signaling were shared between mPMBCL and PMBCL, with SNVs or indels affecting IL4R, STAT6 and SOCS1 found in 37%, 37%, and 89% of mPMBCL and 36%, 40% and 69% of PMBCL, respectively. Moreover, copy number analysis revealed JAK2 amplifications in 44% of mPMBCL (71% of PMBCL) and differential gene expression analysis showed increased levels of CD274 (PDL1), PDCD1LG2 (PDL2) and genes belonging to the JAK-STAT-signaling network in mPMBCL. In contrast, these genetic aberrations were rarely observed in a recent whole-exome sequencing study on 304 primary DLBCL tumors (Chapuy B., Nat.Med. 2018). Mutations were also observed in NF-ĸB pathways but the patterns of mutations were distinct between mPMBCL (BIRC3 and BTK) and PMBCL (NKBIE) suggesting convergent biology with alternative mechanisms of pathway dysregulation. Similarly, mPMBCL harbored different mutations (CD83) implicated in immune evasion compared with PMBCL (B2M). Finally, we compared the mutational landscape of mPMBCL with recently described genetically-defined subgroups of DLBCL. Interestingly, a large majority of mPMBCL harbored at least one of the mutations characteristic of "Cluster 4" (incl. CD83, HIST1H1E, SGK1), a subset of DLBCLs defined by Chapuy et al that predominantly includes GCB-DLBCLs. Conclusion: We have identified and characterized a subgroup of DLBCL that expresses the PMBCL gene expression signature. Similar to bona fide PMBCL, these tumors are characterized by genomic aberrations that affect JAK-STAT, NF-ĸB signaling and immune response. However, our data suggest that dysregulation of the latter two pathways is established through distinct evolutionary modes that are reflected in differential mutation patterns and anatomical and clinical presentations. Our findings provide potential novel therapeutic avenues for this subset of lymphoma. Disclosures Sarkozy: Takeda: Research Funding. Savage:BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Steidl:Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: Filed patent on behalf of BC Cancer; Juno Therapeutics: Consultancy; Tioma: Research Funding; Roche: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy.

Introduction: Grey zone lymphoma (GZL), a B-cell lymphoma with features intermediate between large B-cell lymphoma (LBCL) and classical Hodgkin lymphoma (cHL), is a rare and poorly defined entity. To decipher its mutational landscape and discover new therapeutic targets, we performed exome sequencing of 31 GZL cases. Methods: GZL cases from the LYSA group (N=139) and BC Cancer (N=30) were centrally reviewed and classified as previously published (Sarkozy et al, Am J Surg Pathol 2019). Whole-exome sequencing was performed on 31 cases with available fresh frozen tissue, using laser micro-dissection (LMD, MMI technology) to enrich for tumor cells and obtain matching normal DNA from microenvironment cells. DNA was extracted (Agencourt® DNAdvance kit) and genomic libraries were constructed with the Ovation ultra-low kit (Nugen®). Exome capture was performed using Agilent SureSelectXT V6+UTR followed by paired-end sequencing (NextSeq®). Somatic nucleotide variants (SNVs) and indels were identified using VarScan, Strelka and Mutect. Parameters affecting the sensitivity and specificity of variant calling were optimized using 7 "gold standard" cases for which DNA from peripheral blood cells was additionally available. Possible oncogenic drivers were identified based on rate of recurrence, MutSigCV and literature review. Results: Among the 31 GZL cases, the median age was 41 y (14-83) with a sex ratio of 15M:16F; 21 cases had mediastinal involvement, including 15 within the thymic area; EBER in-situ hybridization (ISH) was positive in 8 cases. Seven (23%) cases were classified as group-0 (cHL morphology with 100% CD20 expression), 22 (71%) with an intermediate morphology as group-1 (N=9, cHL-like morphology) or group-2 (N=13, LBCL-like morphology) and 2 (6%) as group-3 (LBCL with 100% of CD30 expression). The mean coverage was 96X (42-203) for tumor samples. One case was excluded due to failure in the LMD process. Among the 30 cases, 6628 variants across 4826 genes were found, including 2903 coding mutations (325 indels and 2808 SNVs, mean of 104/sample, range: 15-678), 721 affecting the 5' UTR and 2774 the 3' UTR. A total of 152 genes were identified as being potential oncogenic drivers, with a mean of 11 mutated genes per case (range 2-36). The most recurrently mutated genes were SOCS1 (33%), B2M (23%), GNA13 (20%), LRRN3 (17%), and ZNF217, NCOR1, ITPKB, IRF2BP2, CSF2RB, and CSMD3 (13% each). The epigenetic SWI/SNF and transcription regulation pathway (including NCOR1/2, ARID1A, KMT2D, KMT2A) was affected in 73% of the cases, JAK/STAT in 70% and NF-kB in 19%. As assessed by CNVkit and GISTIC, the most recurrent gains/amplifications identified were in 9p24.1 (JAK2, CD274, PDCD2LG2; 69%) and 2p16.1 (REL, BCL11A; 62%), and losses in 11q14.3 (ATM; 48%) and 12q24.33 (NCOR2; 48%). Based on mutational signature analysis, individual base substitutions were linked to mutagenic processes, with the highest contributions associated with aging (29%) and defective DNA mismatch repair (27%); moreover, mutations attributable to AID/APOBEC activity (5%), were found to be significantly enriched in EBV- vs. EBV+ cases (p = 0.013). EBV+ cases had fewer total variants (mean 98 vs 258, p=0.08) and potential oncogenic variants (mean 7 vs 15, p=0.03) compared to EBV- cases. EBV+ cases also lacked mutations in the NF-kB pathway and MHC-class I components (B2M and HLA-B: 0% vs 43% in EBV-, p=0.06) but had mutations in STAT3, DHX58, ACTB and ATP13A4 (6/7 cases) not present in the 23 EBV- cases. LRRN3 and GNA13 mutations were significantly associated with thymic area involvement (40% vs 0%, p=0.01). Furthermore, fluorescence-ISH indicated that 20% (1/5) of EBV+ cases had a rearrangement in the CIITA locus (16p13.13) vs 53% (9/17) in EBV- cases. Patients with an intermediate morphology had more oncogenic variants than those in group 0 and 3 (mean of 15 vs 6 variants/case, p=0.01 affecting 12 vs 5 genes, p=0.004). Finally, NCOR1 (N=4) and NCOR2 (N=2) mutations were exclusively found in cases with intermediate morphology (23% vs 0% for those with group 0 or 3 morphology). Conclusion: These data suggest that GZL is a highly heterogenous disease harboring somatic driver events shared with PMBCL and HL. We also discovered novel gene mutations pointing to the importance of previously unrecognized pathways in the pathogenesis of GZL. The distinct mutational pattern in EBV+ GZL suggests divergent evolutionary trajectories. Disclosures Sarkozy: Takeda: Research Funding. Salles:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; BMS: Honoraria; Amgen: Honoraria, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Savage:BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Steidl:Juno Therapeutics: Consultancy; Tioma: Research Funding; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: Filed patent on behalf of BC Cancer; Seattle Genetics: Consultancy; Bayer: Consultancy.

Approximately 65% of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with standard front-line therapy and achieve an overall survival comparable to the general population. Of the 35% of patients who fail front-line therapy, less than a quarter can be salvaged and cured by intensive chemotherapy followed by an autologous stem cell transplant. Patients who are transplant-ineligible (including elderly patients with co-morbidities, patients who are chemotherapy-refractory or those who have failed transplant) represent an unmet medical need population with a very poor outcome. While chimeric antigen receptor T-cell (CAR-T) therapy has shown promise in this setting, many patients will be unsuitable or relapse after CAR-T therapy. These patients are ideal candidates for less toxic novel therapies and a more tailored personalized approach, recognizing the biological heterogeneity of DLBCL. In this review, we will briefly summarize the standard management options for relapsed/refractory DLBCL and then focus on the novel therapies currently in development. We aim to discuss the biological rationale and available clinical data for the most promising agents, including monoclonal antibodies, antibody-drug conjugates (ADC), pathway inhibitors, immunomodulatory agents and epigenetic modifiers.

Follicular lymphoma is a heterogeneous disease in which some patients present an indolent evolution for decades and others, a rather aggressive form of the disease requiring immediate therapy. While immunochemotherapy has emerged as a standard of care for symptomatic patients, treatment of the asymptomatic population remains controversial. Since the disease is still considered incurable, delayed initiation of therapy is an acceptable option. However, four single injections of rituximab can result in an acceptable clinical response and can improve the duration of the interval without cytotoxic therapy. With recent therapeutic approaches that enable substantial improvements in life expectancy for follicular lymphoma patients, limiting short- or long-term treatment toxicities appears as a new concern in the asymptomatic population. Based on these options, the challenge is to preserve patient quality of life and prolong survival: from the patient's perspective, his/her opinion is therefore of significant importance.

hma.2014.0878 Auteur(s) : Julien Rossignol julien.rossignol3@gmail.com, Clementine Sarkozy, Corinne Haioun, Thierry Lamy, Marion Alcantara, Anne Segolene Cottereau, Christophe Fruchart, Michel Meignan, Vanessa Szablewski, Thierry Molina, Franciane Paul, Emmanuelle Tchernonog, Marc Andre, Olivier Casasnovas, Adrien Grenier, Mathilde Lamarque, Olivier Hermine, Steven Le Gouill AKT : proteine kinase B ATU : autorisation temporaire d’utilisation BTK : Bruton tyrosine kinase BV : brentuximab-vedotine [...]

Mantle cell lymphoma (MCL) is usually an aggressive disease. However, a few patients do have an "indolent" evolution (iMCL) defined by a long survival time without intensive therapy. Many studies highlight the prognostic role of additional genetic abnormalities, but these abnormalities are not routinely tested for and do not yet influence the treatment decision. We aimed to evaluate the prognostic impact of these additional abnormalities detected by conventional cytogenetic testing, as well as their relationships with the clinical characteristics and their value in identifying iMCL. All consecutive MCL cases diagnosed between 1995 and 2011 at four institutions were retrospectively selected on the basis of an informative karyotype with a t(11;14) translocation at the time of diagnosis. A total of 125 patients were included and followed for an actual median time of 35 months. The median overall survival (OS) and survival without treatment (TFS) were 73.7 and 1.3 months, respectively. In multivariable Cox models, a high mantle cell lymphoma international prognostic index score, a complex karyotype, and blastoid morphology were independently associated with a shortened OS. Spleen enlargement, nodal presentation, extra-hematological involvement, and complex karyotypes were associated with shorter TFS. A score based on these factors allowed for the identification of "indolent" patients (median TFS 107 months) from other patients (median TFS: 1 month). In conclusion, in this multicentric cohort of MCL patients, a complex karyotype was associated with a shorter survival time and allowed for the identification of iMCL at the time of diagnosis.

To provide data for future drug evaluation, we analyzed the outcome of 393 patients aged 50 years or older (median, 64 years) with AML in first relapse after treatment in recent ALFA trials. Salvage options were retrospectively classified as follows: best supportive care (BSC), low-dose cytarabine (LDAC), gemtuzumab ozogamicin (GO), intensive chemotherapy (ICT), or ICT combined with GO. Second complete remission (CR2) rate was 31% and median post-relapse survival was 6.8 months (0, 17, 42.5, 53, and 80% and 3.2, 5.6, 8.9, 9, and 19.8 months in BSC, LDAC, GO, ICT, and ICT + GO subsets, respectively). Age, performance status, WBC, CR1 duration, and favorable AML karyotype, but not other cytogenetic or molecular features, influenced post-relapse outcome. Multivariate adjustment and propensity score matching showed that intensive salvage (ICT/ICT+GO/GO versus LDAC/BSC) was associated with longer post-relapse survival, at least in patients with CR1 duration ≥12 months (P = 0.001 and 0.0005, respectively). Of interest, GO appeared to be as effective as standard ICT, and ICT + GO combination more effective than standard ICT. In conclusion, older patients with CR1 duration ≥12 months appeared to benefit from intensive salvage and results observed with GO-containing salvage suggest that GO combination studies should be actively pursued in this setting.

International audience; BACKGROUND: Altered Toll-like receptor (TLR) expression levels and/or mutations in its signaling pathway (such as MyD88 mutation) contribute to the pathogenesis of lymphoproliferative disorders (LPD). CD180 is an orphan member of the TLR family that modulates the signaling of several TLRs, but only limited studies have evaluated its expression by flow cytometry (FCM) in LPD. METHODS: Using a multiparameter FCM approach, we have assessed CD180 mean fluorescence intensity (MFI) in lymph nodes (LNs) and peripheral blood (PB) samples obtained from patients with follicular lymphoma (FL; LN/PB, n = 44/n = 15), chronic lymphocytic leukemia (CLL, n = 26/n = 21), mantle cell lymphoma (MCL, n = 13/n = 17), and marginal zone lymphoma (MZL, n = 16/n = 12). Specimens from non-tumoral PB and LN (n = 8/n = 12) were used as controls. RESULTS: In the LN specimens, FL and control B-cells showed similar CD180 expression (MFI = 1,049 vs. 1,381, P \textgreater 0.05; Mann-Whitney U-test). This level was markedly lower in the other LPDs, MCL (MFI = 396, P \textless 0.05), or CLL (MFI = 502 P \textless 0.05), and similar to MZL (MFI = 858, P \textgreater 0.05). However, the CD180 expression of FL B-cells assessed in PB was dim and/or negative, in the same range as MCL and CLL (FL MFI = 453, MCL MFI = 305, CLL MFI = 420, P \textgreater 0.05) but lower than in MZL (MFI = 895, P \textless 0.05). Therefore, these results suggest a modulation of CD180 expression by neoplastic FL B-cells based on the anatomical compartment. CONCLUSION: These FCM data confirm the usefulness of CD180 in the accurate diagnosis of LPDs and emphasize the need to interpret this marker according to the origin of the sample. (c) 2015 Clinical Cytometry Society

International audience; FDG PET/CT is now validated in non-Hodgkin lymphoma for response assessment in interim and posttreatment lymphoma. We report the case of a 62-year-old man followed by FDG PET/CT for a diffuse large B-cell lymphoma, with initial stage III. The interim FDG PET/CT examination concluded in complete metabolic and morphological response of subdiaphragmatic lymphadenopathy but a persistent abnormal subdiaphragmatic uptake (SUVmax at 9 and Deauville 5-point scale at 5). Therefore, an abdominal biopsy of the corresponding nodules was conducted with a final diagnosis of diffuse fat necrosis

Purpose To study the outcome of histologic transformation (HT) in a large prospective cohort of patients with follicular lymphoma (FL) who previously responded to immunochemotherapy. Patients and Methods After a median 6-year follow-up of 1,018 randomly assigned patients from the PRIMA trial, disease progression was observed in 463 patients, 194 of whom had histologic documentation. Results Forty patients had histology consistent with HT, and 154 had untransformed FL (median time to recurrence, 9.6 v 22.8 months, respectively; P = .018). Thirty-seven percent of biopsies performed during the first year of follow-up showed HT corresponding to 58% of all HTs. Altered performance status, anemia, high lactate dehydrogenase level, “B” symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis were identified as HT risk factors. Response (complete v partial) to immunochemotherapy or rituximab maintenance had no impact on the risk of HT. After salvage treatment, patients with HT had less frequent complete response (50.3% v 67.4%; P = .03) and more disease progression (28.2% v 9.6%; P < .001) than patients without HT. Estimated overall survival for the patients with HT was poorer (median, 3.8 v 6.4 years; hazard ratio, 3.9; 95% CI, 2.2 to 6.9). Autologous stem cell transplantation improved the outcomes of patients with HT (median overall survival, not reached v 1.7 years) but not of patients with persistent FL histology. Conclusion HT in patients with FL who previously responded to immunochemotherapy is an early event associated with a poor outcome that may deserve intensive salvage with autologous stem cell transplantation. These data emphasize the necessity for biopsy at the first recurrence of FL.

To the editor: Follicular lymphoma is typically a disseminated disease with frequent bone marrow infiltration at the time of diagnosis,[1][1] but only a few patients manifest detectable circulating peripheral blood lymphoma cells (CLC).[2][2][⇓][3][⇓][4]-[5][5] We recently described the poor

Introduction: Epigenetic modulation of histones plays a critical role in lymphomagenesis. The histone-methyl transferase EZH2 is the catalytic subunit of the PRC2 complex, and plays an important role in transcriptional repression during germinal center formation. Mutations in EZH2 have been observed in ~20% of DLBCL and aberrant EZH2 activity (in the presence or not of mutation) has been implicated as an oncogenic driver. Tazemetostat is a potent, orally available, selective oral EZH2 inhibitor that demonstrated a favorable safety profile and activity in pts with either EZH2 wild type or mutant B-cell NHL. Elderly pts with a high (2-3) age-adjusted IPI (international prognostic index) represent the most challenging population with the higher primary refractory rate leading to poor overall survival. We report here the safety results of the phase Ib Tazemetostat R-CHOP combination study (Epi-RCHOP, NCT02889523), in pts 60-80 years of age with newly diagnosed DLBCL. Methods: Pts were recruited in LYSA centers and enrolled using 3+3 pts per dose level algorithm to identify the maximum tolerated dose (MTD) and to determine a recommended phase 2 dose (RP2D) of tazemetostat plus R-CHOP. Pts received standard R-CHOP regimen every 21 days in combination with continuous tazemetostat at 400 mg, 600 mg, or 800 mg BID starting on day 2 of R-CHOP cycle 1. For dose escalation purpose, toxicities assigned as dose-limiting toxicity (DLTs) were assessed during cycle 1 and 2 and pts who did not receive at least 85% of tazemetostat-planned doses were not evaluable and replaced. We report here the safety and preliminary pharmacokinetics (PK) data during the DLT period across all doses explored in dose escalation used to determine RP2D. Results: From Oct. 2016 to March 2018, 17 pts were enrolled and started tazemetostat R-CHOP. Median age was 68 years (61-76), 13 (76.5%) had a stage IV disease and 4 a stage III (23.5%), aaIPI was 2 in all patients. Two pts included in the 800mg BID cohort were not evaluable for DLT (and replaced) one due due to noncompliance and one due to lymphoma related hepatic cholestasis. Two other pts had a DLT and discontinued the treatment. The first DLT was a grade 3 right colonic stercoral stasis at 400 mg BID. The second DLT was a grade 5 pneumocystis jirovecii in a context of influenza at 800mg BID. Thirteen pts did not discontinue R-CHOP plus tazemetostat. During cycle 1 and 2, non-hematological adverse events (AE) occurring in ≥10% of the 17 pts, were: gastro-intestinal toxicity (16/17 pts, 94%), infection (6/17, 35%), neurological symptom (6/17, 35%), asthenia (4/17, 24%), pain (4/17, 24%), weight decrease (3/17, 18%), cholestasis (2/17, 12%), dysgeusia (2/17, 12%), hypokalaemia (2/17, 12%), mucosal inflammation (2/17, 12%). Grade 3 or more toxicities observed in more than 10% of the pts were gastro-intestinal toxicity (24%), hypokalaemia and infection (12% each). Beside the 2 DLT, there were 3 events considered as serious AE during the DLT period: 1 grade 2 post lumbar punction syndrome, 1 grade 3 febrile neutropenia, 1 grade 3 hypokalaemia. Importantly, no organ-oriented toxicity increased with tazemetostat dosage escalation (severity and incidence). PK results of doxorubicin (DOX), its major metabolite, doxorubicinol (DOXol), and cyclophosphamide (CP) were compared using the cycle 2/cycle 1 geometric mean ratio (GMR) and 90% confidence interval (CI) for area under the curve (AUC) and Cmax values after R-CHOP alone (Cycle 1) or R-CHOP plus tazemetostat (400 or 800mg, cycle 2). Tazemetostat had no significant impact on DOX and DOXol AUC and although Cmax of DOX was slightly lower in the 800 mg cohort (GMR 0.68; 90%CI 0,47-0.99), Cmax of DOXol was similar (GMR 0.928; 90%CI 0.691, 1.25). CP AUC was similar in the 400 mg cohort (GMR 1.05; 90%CI 0.87-1.26) and slightly lower in the 800 mg cohort (GMR 0.83; 90%CI: 0.77-0.9)) with a similar Cmax (GMR 0.89; 90%CI 0.74-1.07). At 800 mg, AUC and Cmax of tazemetostat were similar compared to single agent study (E7438-G000-101). At the time of data lock (July, 3rd 2018), all the patients (N=7) who had completed the 8 cycles with monitored responses data reached a metabolic complete response. Conclusion: R-CHOP plus tazemetostat is generally well tolerated; safety and PK results appear comparable to R-CHOP alone. A RP2D of tazemetostat combined with R-CHOP would be 800 mg BID, consistent with the same daily dose as all tazemetostat monotherapy studies in adults. Disclosures Sarkozy: Roche/Genentech: Consultancy. Morschhauser:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy. Suttle:Epizyme: Employment. Karlin:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tilly:Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees. Herbaux:Gilead Sciences, Inc.: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Salles:Takeda: Honoraria; Pfizer: Honoraria; Merck: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; Servier: Honoraria; Morphosys: Honoraria; Acerta: Honoraria; AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Ribrag:argenX: Research Funding; NanoString Technologies: Consultancy, Honoraria; MSD: Honoraria; pharmamar: Other: travel; epizyme: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Amgen: Research Funding; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Incyte Corporation: Consultancy; BMS: Consultancy, Honoraria, Other: travel.

INTRODUCTION There is a growing interest in analyzing the biological and clinical variables that might help in identifying patients at risk of histological transformation (HT), a critical event that can still lead to reduced survival in patients with follicular lymphoma (FL). As part of the Aristotle study, we have previously reported that the risk of HT as a first event has been significantly reduced by the use of rituximab (Federico et al, Lancet Hematology 2018). However, this incidence might still be unacceptable in some groups of patients. Thus, we investigated the risk of HT in patients with primary refractory FL, a subset of patients with poor prognosis. METHODS We carried out a retrospective analysis of cumulative incidence of HT in the 289 cases with primary refractory FL retrieved from the Aristotle Study, which included a total of 6970 FL cases (grade 1, 2 or 3a), diagnosed between 1997 and 2013 and treated with systemic therapy. Refractoriness was defined as progressive disease (PD) within the end of first-line therapy. Patients with PD were compared to patients with partial response (PR) or stable disease (SD) and to patients with complete response (CR) at the end of therapy. The cumulative incidence of HT was calculated using the Nelson-Aalen estimator, with a 95 confidence interval (CI). The estimate is in absolute value, and then multiplied by 100. The overall survival (OS) and survival after relapse/progression (SAR) were calculated using Kaplan-Meier estimation, with a 95% CI. RESULTS Six hundred and twenty-eight cases (9%) were excluded for incomplete data and 6,339 were considered for analysis. The five-year cumulative incidence of HT among patients with PD was 34.2% (95% CI: 26.9-43.4), whilst it was 7.1% (95% CI: 6.0-8.5) and 3.5% (95% CI: 3.0-4.2) in the 1,954 and 4,096 patients with PR+SD and CR at the end of induction therapy, respectively. The rate observed in PD group had a Hazard Ratio (HR) of 11.4 (95CI: 8.61-15.0) compared with CR patients, and 6.14 (95% CI: 4.6-8.2), when compared with PR+SD patients. All comparisons and estimations showed a p-value below 0.001. Cumulative incidences of HT according to response to initial therapy are represented in Figure 1. The five-year SAR was 33% (95% CI: 28-39) for the PD group, with a median SAR of 1.1 year (95% CI: 0.8-1.8). At the same time point, the SAR was 56% (95% CI: 53-60) in patients with initial PR/SD, with a median SAR of 6.3 years (95% CI: 5.7-8.6). Finally, in patients with initial CR who later relapsed, the 5 year SAR was 63% (95% CI: 66-72), with a median of 10.4 years (95% CI: 10-12.2). The difference among groups was statistically significant (p-value CONCLUSIONS According to the results of the present study, primary refractory FL patients have not only an already known reduced SAR (Casulo et al, JCO 2015), but also a dramatically increased risk of HT, which probably contributes to patients' adverse outcome. These findings reinforce the need to develop combined diagnostic and therapeutic strategies aimed to eradicate the disease at the "first shot", reducing the risk of refractoriness and eventually further improving the outcome of FL patients. Disclosures Sarkozy: ROCHE: Consultancy. Wondergem:NOVARTIS: Other: advisory board, educational talk; SANOFI: Other: advisory board; GILEAD: Other: educational talk. Chamuleau:Genmab: Research Funding; BMS: Research Funding; celgene: Research Funding; Gilead: Research Funding. Gomes da Silva:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Celgene: Other: Travelling support; Roche: Other: Institution's payment for consultancy, Travelling support; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Holte:Roche, Norway: Research Funding; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Zucca:CELGENE: Other: Grant to the Institution + Advisory Board; Janssen: Other: Grant to the Institution; ROCHE: Other: Grant to the Institution + Advisory Board; Celltrion Healthcare + Mei Pharma + Astra Zeneca: Other: Advisory Board; AbbVie + Gilead: Other: Travel Expenses; Gilead + Bristol-Myers Squibb + MDS: Other: Expert Statement + Meetings. Aurer:Roche: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Marcheselli:Fondazione Italiana Linfomi (FIL) Onlus: Employment. Salles:Novartis: Consultancy, Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Morphosys: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Other: Advisory Board, Research Funding; Pfizer: Honoraria; Gilead: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Servier: Honoraria.

Introduction : Follicular lymphoma (FL) is a clinically and genetically heterogeneous disease with highly variable patient outcomes. Recently, Huet et al. proposed a 23-gene expression-based risk score for predicting progression-free survival (PFS) in FL patients treated with rituximab and chemotherapy (Huet et al. Lancet Oncology 2018). The m7-FLIPI risk score has also been described as a clinico-genetic model predicting patient outcomes (Pastore et al. Lancet Oncology 2015). Moreover, EZH2 wild-type status and high expression of the FOXP1 transcription factor are associated with increased risk of lymphoma progression (Mottok et al. Blood 2018). This multitude of prognostic tools in FL raises the question whether they identify common biology. The aims of this study were to assess whether the 23-gene predictor score identifies a poor risk group of patients in our own gene expression dataset, and whether commonality exists between the 23-gene score, the m7-FLIPI, EZH2 mutation status and FOXP1 expression. Methods: In our previous work, we generated Illumina DASL microarray expression profiles for 137 FL patients who were treated with rituximab and CVP chemotherapy (cyclophosphamide, vincristine and prednisone). Using genes from the 23-gene linear risk predictor, we determined each patient's risk score by setting coefficients at -1 and +1 for genes associated with favorable and unfavorable PFS, respectively. We dichotomized the distribution of scores using the maximally selected log-rank statistic. We also performed unsupervised, hierarchical clustering to identify underlying subgroups in an unbiased fashion. Survival analyses were performed using the log-rank test and Cox regression analyses. We used gene set enrichment analysis to identify concordant differences of relevant gene signatures between specimens with either low or high expression of FOXP1. Results : Twenty genes from the 23-gene predictor (87%) were identified in the DASL gene expression dataset. The coefficients from univariate Cox regression analysis from our data were correlated with coefficients from Huet et al. (Pearson r = .7, P < .001; Spearman r = .44, P = .051). All poor-risk genes from the 23-gene predictor were associated with poor PFS in our data, and vice versa. Concordantly, calculated risk scores were significantly associated with PFS in the univariate Cox regression analysis (P = .007). Dichotomizing the distribution of risk scores identified 68% of cases with high risk score who had inferior PFS and OS compared to 32% of cases with low risk score (5-year PFS 54% vs. 77%, P = .004; 5-year OS 73% vs. 86%, P = .04). Hence, the risk score stratified patients into groups with diverging outcomes. This association was found to be independent of the Follicular Lymphoma Prognostic Index (FLIPI). In addition, the mean risk score was significantly higher in cases with high expression of FOXP1 (P < .001) and in cases with high m7-FLIPI risk score (P = .023). Unsupervised hierarchical clustering identified two main clusters ("cluster 1" and "cluster 2") that were characterized by low and high expression of genes associated with poor outcome, respectively. Patients from "cluster 2" experienced worse PFS compared to patients in "cluster 1" (P = .046; 5-year PFS 54% vs. 68%). The 5-year OS was 72% for patients in "cluster 2", vs. 81% in "cluster 1" (P = .13). We have previously reported that a germinal centre dark zone signature is enriched in cases with high FOXP1 expression, and the ICA13 signature reported by Huet et al. has been described as being highly expressed in centroblasts. Using gene set enrichment analysis, we found that genes with positive weight and coefficients in the ICA13 and the 23-gene predictor score, respectively, were enriched in the FOXP1-high phenotype (adjusted P = .009 and .005, respectively). GeneMANIA illustrated co-expression interconnectivity among ORAI2, TCF4, AFF3, FOXO1, CXCR4 and FOXP1, suggesting that genes with prognostic significance operate in tightly regulated networks. Conclusions: Our results exemplify the robustness of the predictor model by Huet et al. Further, we demonstrate biomarker convergence on a common phenotype: FOXP1 expression, EZH2 wild-type status and expression of dark zone-related genes, which characterize a subset of FL cases with adverse outcome following rituximab and chemotherapy. Disclosures Sarkozy: Roche/Genentech: Consultancy. Sehn:Roche/Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Weigert:Novartis: Research Funding; Roche: Research Funding. Steidl:Juno Therapeutics: Consultancy; Tioma: Research Funding; Bristol-Myers Squibb: Research Funding; Roche: Consultancy; Seattle Genetics: Consultancy; Nanostring: Patents & Royalties: patent holding.

Introduction: standard treatment for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) but this strategy is not appropriate for elderly DLBCL patients (pts) related to a high risk of toxicities. Multiple chemotherapy regimens had been developed for heavily pretreated elderly DLBCL patients such as R-bendamustine, R-gemcitabine-oxaliplatin (R-GEMOX) and pixantrone; the median progression free survival (PFS) of these regimens were 2, 4 and 3.5 months, respectively in prospective phase II studies for patients previously treated with R (Sehn 2017, Mounier 2013, Pettengel 2016). Adapted dose of ifosfamide and etoposide was firstly developed as sequential consolidation regimen after high-dose CHOP (ACVBP regimen) in first line therapy of young DLBCL patients (Tilly 2003). This regimen with a safe toxicity profile was then used in combination with R in Lyon University Hospital in elderly R/R DLBCL ineligible to intensive strategy. Methods: we retrospectively reviewed the efficacy and the safety profile of this regimen performed in two Lyon University Hospitals (Centre Hospitalier Lyon Sud and Leon Berard Cancer Center). Between June 2004 and March 2017, 75 pts with R/R DLBCL (63 de novo DLBCL, 12 transformed DLBCL) received R (375 mg/m2) in combination etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) on day 1 (N=72, 96%) and on days 1-2 (N=3, 4%) at 2 (N=46, 61%) or 3-week (N=29, 39%) intervals. All medical records were reviewed for clinical and biological characteristics, modality of treatment and supportive care, toxicities, responses and outcome. Results: the median age was 79 years (range, 64-92) at the beginning of R-ifosfamide/VP16 treatment with 46% of the patients over 80 years. 13% of pts had a CIRS-G grade 3 or 4 >2 categories and 35% had a cumulative CIRS-G score more than 6. The performance status according to EORTC scale was 2-4 in 37% of the pts and 93% had III-IV Ann Arbor stages. Age-adjusted IPI were 0-1 in 20 pts (27%) and 2-3 in 55 pts (73%). All patients were previously treated in first-line therapy by R in combination with chemotherapy (CHOP, N=56, 75%, low-dose CHOP, N=14, 19%, other, N=5, 6%). The patients received a median number of 1 previous line (range, 1-8) and no patient was previously treated by ASCT. The median time between initial diagnosis and R-ifosfamide/VP16 was 20 months (range 4-187). The median time between the last treatment and R-ifosfamide/VP16 was 5 months (range 0-181). A refractory disease to first-line treatment was showed in 14 pts (19%). 31% of the patients had a refractory disease to the last regimen performed before R-ifosfamide/VP16. Patients received a median of 6 cycles (1-12). At the end of treatment, the overall response rate (ORR), defined by the rate of complete response (CR) and partial response (PR) was 37%, with 18% of CR. Evaluations were assessed for 29% of the pts by TEP scanner. For toxicity, among the 387 cycles, 10 patients developed febrile neutropenia (2.6%); 15 (20%) a grade 3-4 neutropenia; 7 (9%) a grade 3-4 thrombocytopenia; 5 patients needed platelet units and 16 patients received packed red blood cell units. No grade 3-4 non-hematological toxicity was observed and no toxic death occurred. With a median follow up of 31.3 months (range, 5.0-202.8), the median progression-free survival (PFS) was 4.3 months with a 1-year PFS rate of 26.0% (95%CI, 17.7-38.3) (Figure 1A). The median overall survival (OS) was 8.2 months with a 1-year OS rate of 40.8% (95%CI, 30.9-54.0) (Figure 1B). The median duration of response was 4 months (range 1-97). The median PFS was adversely affected by response (refractory versus CR/PR) to the last treatment (3.0 months versus 5.5 months, P=0.001) (Figure 1C). Conclusions: in this retrospective study, R-Ifosfamide/VP16 regimen provided effective results in R/R DLBCL transplant-ineligible pts with 37% of ORR and a median of PFS of 4.3 months with a safe toxicity profile. This regimen could also be considered as a platform for combinations with novel targeted agents in these categories of patients. Disclosures Karlin: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sarkozy:ROCHE: Consultancy. Bachy:Gilead Sciences: Honoraria; Takeda: Research Funding; Sandoz: Consultancy; Amgen: Honoraria; Roche: Research Funding; Celgene: Consultancy; Janssen: Honoraria. Salles:Abbvie: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Novartis: Consultancy, Honoraria; Servier: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria. Ghesquieres:Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy.

Purpose International Prognostic Index (IPS) is the most widely used risk stratification index for advanced stage Hodgkin's lymphoma (HL). The use of (18F)-fluorodeoxyglucose PET/CT at diagnosis allows a better characterization of extra-nodal involvement (ENI). We investigated if the type of ENI could affect the prognosis of stage IV HL patients diagnosed with PET/CT and if a specific prognostic index could be defined for these patients (pts). Patients and methods We retrospectively analyzed 220 stage IV HL patients treated from 2005 to 2015 in three LYSA centers. We considered the local investigator interpretation based on the nuclear medicine physician PET/CT report. Regarding ENI, six subgroups were identified: involvement of lung and/or pericard and/or pleural, liver, diffuse and/or focal bone involvement, digestive system, and other involvements; we also considered bone marrow involvement based on the results of bone marrow biopsy. The main outcome was event free survival (EFS) defined by relapse, progression, death from any cause and initiation of a new therapy. For prognostication, we first evaluated the six variables of IPS-6 (corresponding to IPS without "stage IV" item) in this population. ENI was tested adjusted on the retained IPS variables. Univariate and multivariate Cox models were used to assess their prognostic ability for EFS. Cross-validation (10-fold) was used to select the more robust variables avoiding optimism. The finally selected variables constituted a score that was tested on overall survival (OS). Results Among the 220 stage IV patients, 135 (61%) were male. Median age was 33 years (range, 16-86) and 72 pts (33%) were ≥45 years. 130 pts (59%) presented constitutional symptoms. Nodular sclerosis subtype was observed in 163 pts (74%), mixed cellularity subtype in 25 pts (11%) and 47/157 pts (30%) presented EBV-positive HL. For biological parameters of IPS, 158 pts (80%) had low albumin level 15G/L in 42pts (19%) and lymphocyte count Conclusions: For stage IV HL defined by PET/CT, we developed a simple prognostic score based on age (≥45y) and liver involvement that identify a subgroup of patients with a poor outcome. These findings need to be validated in independent cohorts. Based on these results, whether HL pathogenesis differs by ENI sites should be investigated. Disclosures Bachy: Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Honoraria. Karlin: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, Other: travel support; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Sarkozy:ROCHE: Consultancy. Traverse-Glehen:Takeda: Research Funding; Astra Zeneca: Other: Travel. Salles:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Servier: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria; BMS: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Janssen: Honoraria, Other: Advisory Board; Abbvie: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Epizyme: Honoraria; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Merck: Honoraria; Servier: Honoraria; Takeda: Honoraria. Casasnovas:Takeda: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy; Roche: Consultancy, Research Funding; Bristol-Meyers Squibb: Consultancy; Merck: Consultancy. Ghesquieres:Celgene: Consultancy; Gilead: Consultancy; Sanofi: Consultancy.

The aim of this review is to describe the outcome of primary refractory diffuse large B cell lymphoma in the rituximab era and the different therapeutic options as well as new biological markers that could allow the pathologist to distinguish these cases at diagnosis.Diffuse large B cell lymphoma outcome has been impressively improved since the introduction of rituximab in association with anthracycline-based chemotherapy; however, primary refractory patients still represent an unmet medical need.If patients without relapse after 2 years from diagnosis have an outcome comparable to healthy individuals, primary refractory patients still represent 20% of the cases with a very poor overall survival. These cases are usually described as progressive patients during first line or patients reaching a nonadequate partial response or those relapsing within a year after reaching a response.

International audience; The probability to develop non-Hodgkin lymphoma grows with age. The biological links between aging and lymphoma are not well described in the literature, and different hypothesis may be raised to explain this complex relationship. First, the impact of chronological age favoring the accumulation of genetic alterations can contribute to the multisteps proces of lymphomagenesis. Then, the age-related defects in cancer protection and the age-related clonal restriction in hematopoietic stem cell may also promote lymphoma development. Finally, the senescent and immunosenescence phenotype might represent a key process explaining this link. In this review, we will explore the current available clinical data and their ability to apply to age-related regulation pathways.

International audience; Double-hit lymphoma (DHL) is a subgroup of aggressive lymphomas with both MYC and BCL2 gene rearrangements, characterised by a rapidly progressing clinical course that is refractory to aggressive treatment and short survival. Over time, the definition was modified and now includes diffuse large B-cell lymphoma (DLBCL) with MYC translocation combined with an additional translocation involving BCL2 or BCL6. Some cases that have a similar clinical course with concomitant overexpression of MYC or BCL2 proteins were recently characterised as immunohistochemical double-hit lymphomas (ie, double-protein-expression lymphomas [DPLs]). The clinical course of these DPLs is worse than so-called standard DLBCL but suggested by some studies to be slightly better than DHL, although there is overlap between the two categories. Present treatment does not allow cure or long-term survival in patients with genetic or immunohistochemical double-hit lymphomas, but several new drugs are being developed.

The outcome of patients with follicular lymphoma (FL) has improved over the last two decades through the introduction of anti-CD20 monoclonal antibodies, usually used in combination with chemotherapy. However, patients with FL still experience multiple relapses, requiring several lines of treatment. Early toxicity of chemotherapy is a significant concern and as the life expectancy of patients with FL is increasing, late toxicities become an increasingly important concern. Progress made in understanding the biology of FL, especially dysregulation of intracellular pathways and immunological antitumor responses, recently allowed for the development of innovative chemo-free therapeutic approaches. In this report, different options such as new anti-CD20 antibodies, antibodies targeting other cell surface antigens, bi-specific antibodies, immunomodulation, idiotype vaccine and other targeted therapies are presented. The article also highlights how, although promising in early phase studies, the cost-effectiveness of new agents will have to be justified in Phase III trials. Furthermore, chemo-free regimen might not mean toxicity-free treatment and monitoring of early and late toxicities is required.

Les lymphomes B diffus a grandes cellules (LBDGC) comportant un rearrangement chromosomique du gene MYC representent environ 10 % des LBDGC. Ils sont souvent refractaires aux therapeutiques standards et associes a un pronostic pejoratif. L’indication d’une etude cytogenetique par hybridation in situ en fluorescence (FISH) pour identifier ces cas n’est pas consensuelle. C’est pourquoi nous avons compare 45 cas de LBDGC avec rearrangement du gene MYC (MYC + ) a 45 cas sans rearrangement (MYC−) dans une etude retrospective realisee a partir des archives du service d’Anatomie Pathologique du Centre Hospitalier Lyon-Sud. Le rearrangement du gene MYC etait detecte par technique de FISH a l’aide d’une sonde break-apart (SPEC MYC–Zytovision®). La presence du rearrangement etait comparee aux donnees cliniques (âge, sexe, antecedent de lymphome folliculaire, localisation), morphologiques (type histologique, architecture, aspect en ciel etoile, variante cytologique) et immunohistochimiques (phenotype centrofolliculaire ou post-germinatif, Ki67, BCL-2, BCL-6, MYC). Le phenotype etait evalue par immunohistochimie selon l’algorithme de Hans et par technique de Reverse Transcriptase Multiplex Ligation-dependent Probe Amplification (RT-MLPA). Concernant la presentation clinique, il n’y avait pas de difference statistiquement significative entre les deux groupes. Une morphologie intermediaire (lymphome de Burkitt/LBDGC) et une cytologie immunoblastique etaient plus frequentes dans le groupe MYC+ (respectivement 20/45 cas, 44 % et 17/45, 38 %) que dans le groupe MYC- (8/45 cas, 18 % et 6/45, 13 %) (p

Diffuse large B-cell lymphoma (DLBCL) is the most common form of aggressive non-Hodgkin lymphoma, accounting for 30-40% of newly diagnosed cases. Obesity is a well-defined risk factor for DLBCL. However, the impact of body mass index (BMI) on DLBCL prognosis is controversial. Recent studies suggest that skeletal muscle wasting (sarcopenia) or loss of fat mass can be detected by computed tomography (CT) images and is useful for predicting the clinical outcome in several types of cancer including DLBCL. Several hypotheses have been proposed to explain the differences in DLBCL outcome according to BMI or weight that include tolerance to treatment, inflammatory background and chemotherapy or rituximab metabolism. In this review, we summarize the available literature, addressing the impact and physiopathological relevance of simple anthropometric tools including BMI and tissue distribution measurements. We also discuss their relationship with other nutritional parameters and their potential role in the management of patients with DLBCL.

BACKGROUND Renal involvement in light chain (LC) deposition disease (LCDD) is typically characterized by nodular glomerulosclerosis and nephrotic range proteinuria. Rare cases of LCDD without glomerular symptoms have been reported, but clinical and pathological characteristics of this entity remain poorly described. METHODS This multi-centre retrospective study included 14 patients with biopsy-proven renal LCDD and proteinuria

International audience; Follicular Lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) subtype and its course is heterogeneous. At diagnosis, some patients with FL manifest a detectable leukaemic phase (FL-LP), but this feature has been seldom described and is poorly characterized. Among 499 patients diagnosed with FL in Lyon-Sud hospital, 37 (7·4%) had characteristic FL-LP (by cytological blood smears and flow cytometric analysis). In addition, 91/1135 FL patients from the PRIMA study presented FL-LP at study entry. In order to evaluate the outcome of this Lyon-Sud cohort, FL-LP patients were matched with 111 newly diagnosed FL without LP according to the Follicular Lymphoma International Prognostic Index (FLIPI) score, age and treatment. Presence of FL-LP was associated with shorter progression-free survival (PFS) and overall survival (OS) (P = 0·004 and P = 0·031, respectively). Presence of FL-LP and high FLIPI score remained independent prognostic factors in a Cox model for time to progression (TTP). A number of circulating lymphoma cells (CLC) >4 × 109/l was the most significant predictor for a shorter TTP in this Cox model. The prognostic impact of FL-LP on TTP was validated in the PRIMA cohort (P = 0·0004). In conclusion, FL-LP is a rare event associated with shorter PFS and patients with CLC >4 × 109/l have a poorer outcome. These patients should be monitored carefully to consider alternative therapeutic options.

INTRODUCTION: The benefits of ibrutinib (ibr) have been demonstrated by the phase 3 RESONATE and RESONATE-2 trials for patients (pts) with R/R and TN (≥ 65 years) CLL, respectively. In these studies, ibr showed significantly improved progression-free survival (PFS) and overall survival (OS) vs approved comparators (ofatumumab [ofa] in RESONATE and chlorambucil [clb] in RESONATE-2). However, a number of other treatment regimens are widely used in clinical practice for CLL based on individual patient and disease characteristics; it is currently unknown if ibr results in better survival outcomes when compared directly with each of these other treatments. AIM: In the absence of a head-to-head comparison, we investigated the relative efficacy of ibr vs physician's choice (PC) in pts with R/R or TN CLL by comparing pt-level data from RESONATE and RESONATE-2 with data from pts in a real-world setting (the Lyon-Sud database). This database holds electronic medical records for 390 pts with CLL from the academic Lyon-Sud Hospital in France; nearly all patients were diagnosed between 1990 and 2014. This is the first analysis of ibr vs PC in a real-world setting for pts with TN CLL. METHODS: Pt-level data from RESONATE (ibr, n = 195; ofa, n = 196) were compared with data on pts with CLL from Lyon-Sud who received 2nd(n = 107) or later-line treatment (3rd [n = 62], 4th [n = 43], and subsequent [n = 51] lines). Similarly, RESONATE-2 (ibr, n = 136; clb, n = 133) pt-level data were compared with those of pts aged ≥ 65 years who received 1st-line treatment (n = 131). In order to account for non-comparability due to lack of randomization, a multivariate Cox proportional hazards model was used to compare PFS and OS between treatments, including line of therapy, age, sex, disease stage (based on Binet/Rai), and deletion 17p or 11q mutations as covariates. For the definition of PFS, missing data for date of disease progression for pts in Lyon-Sud who initiated subsequent therapy were replaced by the conservative proxy of date of initiation of next treatment. Predicted PFS and OS curves for the Lyon-Sud cohort were derived from the multivariate model. RESULTS: For R/R pts in Lyon-Sud, across all treatment lines the most frequent regimens used were rituximab (R) + chemotherapy (n = 46), bendamustine + R (BR; n = 28), fludarabine + cyclophosphamide + R (FCR) (n = 27), clb + R (n = 19), R monotherapy (n = 21), and R-CHOP-based (n = 19); the remaining percentages comprised various other therapies, each used in < 5% of pts. Median age at treatment initiation for Lyon-Sud and RESONATE was 69 and 67 years, respectively; median number of prior therapies was 2 and 3, and median follow-up was 30.0 and 21.9 months. More lines of prior therapy, older age, male sex, advanced disease stage (Binet C/Rai III/IV), and presence of deletion 17p/11q were independent risk factors for worse PFS and OS outcome. After adjustment for differences in baseline characteristics, PFS and OS hazard ratios (HRs) for ibr vs PC were 0.18 (95% confidence interval [CI], 0.13-0.26) and 0.28 (0.17-0.46), respectively. Adjusted HRs for ibr vs the most frequent treatments ranged from 0.09 (R monotherapy) to 0.38 (FCR) for PFS and 0.21 (R monotherapy) to 0.33 (FCR) for OS; all were statistically significant. For TN pts in Lyon-Sud, the most frequent treatment regimens used were FCR (n = 40), clb + R (n = 21), clb monotherapy (n = 17), R-(mini)CHOP (n = 11), and BR (n = 11). Median age at treatment initiation was 73 years for both Lyon-Sud and RESONATE-2; median follow-up was 36.9 and 28.1 months, respectively. Older age, male sex, and advanced disease stage were independent risk factors for worse PFS and OS outcome. After adjustment for baseline differences, the PFS and OS HRs for ibr vs PC were 0.25 (0.14-0.47) and 0.41 (0.17-0.99). Predicted PFS and OS curves for both R/R and TN patients are presented in Figure 1. CONCLUSIONS: Investigation of survival outcomes suggests that ibr administered to pts in RESONATE and RESONATE-2 was more effective than PC used in a real-world cohort of French pts with R/R or TN CLL, suggesting a 4.8-fold improvement in PFS and a 3.4-fold improvement in OS in R/R pts and 4-fold and 2.4-fold improvements in TN pts, respectively. These results further support the growing evidence that ibr significantly improves both PFS and OS vs commonly used regimens in the R/R and TN settings, and could have important implications for improving treatment of CLL in clinical practice. Disclosures Salles: Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Mundipharma: Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding. Sarkozy:Sandoz: Research Funding; Janssen Research & Development: Honoraria; Gilead: Honoraria; Takeda: Research Funding. Ghesquieres:Mundipharma: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche France: Research Funding. Diels:Johnson & Johnson: Employment, Equity Ownership. Besson:Janssen: Employment. MacDougall:Janssen Research & Development: Research Funding; IMS Health: Employment. Hermans:Janssen Research & Development: Research Funding; IMS Health: Employment. Healy:Janssen Research & Development: Employment. Garside:Janssen Research & Development: Employment. Iraqi:Janssen Research & Development: Employment.

Treatment of relapsed/refractory peripheral T-cell lymphoma (R/R PTCL) remains an unmet medical need, as treatment with polychemotherapy is associated with poor outcome. With the exception of Brentuximab vedotin in systemic anaplastic large cell lymphomas, recent FDA approved drugs to treat R/R PTCL showed limited activity, with a 30% overall response rate (ORR), a complete response (CR) rate of 10-15% and short remission duration. Recurrent mutations of TET2 or other genes involved in DNA methylation regulation have recently been described in PTCL, especially in angioimmunoblastic T cell lymphomas (AITL) where TET2 mutations are present in 50-70% of patients. These molecular anomalies are also present in myeloid malignancies, which can be sensitive to treatment with hypomethylating agent. However, efficacy of hypomethylating agent in PTCL is unknown. We report here the results of 5-Azacytidine (5-AZA) treatment in 19 R/R PTCL patients. Two of them have been previously published (Cheminant et al. BJH 2015; Saillard et al. Hematol Oncol 2016). Treatment was administered between January 2013 and July 2016 according to physician decision and consisted in subcutaneous injection of 75 mg/m² 5-AZA during 7 consecutive days every 28 days, until progression or unacceptable toxicity. Six patients received rituximab for 4-8 infusions because of EBV-DNA positivity. Evaluation was performed locally according to IWG guidelines. Baseline characteristics of patients are presented in table 1. All patients presented with adverse prognostic factors and 17 patients had R/R PTCLs. Ten patients had previous or concomitant diagnosis of myelodysplastic syndrome, mostly (9/10) chronic myelomonocytic leukemia (CMML). Two patients did not receive chemotherapy before 5-AZA because of the presence of an associated CMML that required treatment first for myeloid malignancy, according to physician decision. Patients received a median number of 3 cycles of 5-AZA [1 - 43] and, at time of analysis, 7 patients are under therapy (Figure 1). Hematological toxicity was as expected. Two patients developed unusual adverse reaction: grade 2 polyneuropathy (which was deemed to be related to paraneoplastic syndrome) and grade 3 diarrhea of unknown origin, the latest leading to treatment interruption. The median follow-up was 84 days [19 - 1236]. Overall response rate (ORR) for the entire population was 53% (10/19), but was significantly higher in AITL patients than in patients with other PTCL entities (9/12, 75% vs. 1/7, 15%, p=0,0198). Among these 10 responding patients, 5 patients - all suffering from AITL - reached complete response (CR), leading a CR rate of 42% in this entity. Three additional patients were in stable disease (best response) and 6 progressed rapidly. It is noteworthy that among the 9 AITL patients who responded, only 2 patients experienced progression after 86 and 499 days, respectively, the remaining 7 patients being still responders and under therapy. None of the patients with another PTCL entity experienced response, with the exception of one patient with ATLL for whom 5-AZA induced a rapid and profound decrease in lymphocyte count; however, this patient relapsed after the second cycle. TET2 was sequenced in 14 patients and was mutated in 8/10 (80%) AITL and 1/4 (25%) other PTCL. Interestingly, 8/8 AITL patients with TET2 mutational status available who experienced a response after 5-AZA treatment were TET2 mutated. In summary, 5-AZA treatment is associated with significant response rate in R/R AITL, including prolonged CR. Additional genomic analyses are ongoing and will be presented during the meeting, aiming to correlate response rate with mutational status in the TET2, IDH2 and DNMT3A epigenetic modifier genes. Finally these results warrant further prospective studies evaluating 5-AZA treatment in R/R AITL or R/R PTCL bearing mutations in epigenetic modifiers. Table Clinical characteristics of 19 PTCL patients Table. Clinical characteristics of 19 PTCL patients Figure 5-AZA response in PTCL patients Figure. 5-AZA response in PTCL patients Disclosures Dupuis: janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Sarkozy:Janssen Research & Development: Honoraria; Sandoz: Research Funding; Takeda: Research Funding; Gilead: Honoraria. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Hermine:AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Celgene: Research Funding; Alexion: Research Funding; Novartis: Research Funding. Haioun:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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.

Although progression free survival and overall survival of patients with Hodgkin lymphoma (HL) has improved with modern treatment in the past 10 years, 10 % of patients will fail to conventional therapy and die of their lymphoma. The search of new prognostic factors for identifying these high risk patients at diagnosis of HL remains challenging in daily practice. The evaluation of the tumor microenvironnement was shown to help identifying a subset of patients treated with ABVD having a high risk of treatment failure (Tan KL et al, Blood 2012). PET positivity after 2 cycles of chemotherapy allows also identifying a subset of patients with poor outcome (Gallamini, JCO 2007) and PET-guided strategy were developed to improve the management of HL patients in order to either intensify treatment for high risk patients or deescalate treatment for sparing the others from toxicities. The aim of this study was therefore to evaluate the impact of baseline tumor microenvironnement in a large cohort of HL patients prospectively treated with upfront escalated BEACOPP in a randomized phase III clinical trial evaluating a PET-driven strategy (AHL 2011, NCT01358747) and to compare its prognostic value with other clinicopathological markers. Material and Methods Tumoral material was collected from May 2011 to May 2014 from HL patients prospectively enrolled in the AHL 2011 study. The AHL 2011 trial was designed to evaluate in 16-60 years old HL patients with Ann Arbor stage III, IV or high risk IIB, a de-escalade PET-driven strategy after 2 cycles of BEACOPPesc randomly compared to a standard treatment not driven by PET and delivering 6 cycles of BEACOPPesc. PET were centrally reviewed and interpreted according to Deauville criteria. As recently reported (Casasnovas, ASH 2015 Abs 577), the 2y-PFS was similar in the PET-driven (88%) and the standard arm (91%; p =0.79). The tumor microenvironnement was analyzed on formalin fixed paraffin embedded lymph node biopsy obtained for the diagnosis before treatment by morphological evaluation on standard staining (% polynuclear eosinophils, % lymphocytes, % plasmocytes, % histiocytes), and immunohistochemistry (IHC) scoring (score 0-1-2-3) for CD20, CD3, CD68-TAMs (tumor-associated macrophages) and CD163 and were centrally reviewed. Percentage of tumoral cells and EBV status were also analysed. In this analysis, the prognosis value of tissue markers expressions were compared to those of clinical and biological patient's characteristics, and PET results after 2 cycles of escalated BEACOPP. Results Six hundred fifty eight patients with available IHC data out of 823 enrolled in AHL2011 study were included in the analysis. With a median follow-up of 16.1 months, 2-year PFS was 89.4% (95% CI [86.2% ; 91.9%]) and 2-year OS 98.7% (95% CI [96.4% ; 99.5%]). In univariate analysis male gender, at least one extra-nodal involvement, B symptoms, Hemoglobin Among baseline patients characteristics, male gender, hemoglobin In conclusion, CD68 expression was confirmed to be an important prognostic marker in this large prospective cohort of patients treated with upfront escalated BEACOPP in a modern PET-guided strategy. Baseline high CD68 expression is associated to a higher risk of PET2 positivity and the combination of this microenvironment marker and PET2 results allowed identifying a population of patients with high risk of treatment failure. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Brice: Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Bristol Myers-Squibb: Honoraria; Seattle Genetics: Research Funding; Gilead: Honoraria; Roche: Honoraria. Casasnovas:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding.

Background There is no standard treatment for R/R MCL that fail first line treatment. Non cross resistant regimens are usually used, which provided sometimes good overall response rate (until 93%) but with a minor disease control (PFS Aim To explore the efficacy of the RiBVD regimen in the salvage therapy setting following failure of one, two or more prior treatments. Methods We proposed to all French LYSA partner centers a survey to retrospectively evaluate the efficacy of the RiBVD regimen in R/R MCL patients, regardless of prior treatments used. The RiBVD regimen comprises : Rituximab 375mg/sqm D1, Bendamustine 90mg/sqm D1 and D2, bortezomib 1,3mg/sqm D1, D4, D8, D11 and dexamethasone 40 mg D2. Analysis was performed in June 2016. Results From January 2012 to December 2015, 49 patients from 17 French hematological centers were recruited to the study. The median age was 72 years (50-91y) with 14 young ( 65y). Thirty eight cases presented with classic MCL variant and 11 had a blastoid variant. All patients but one were CD20+, CD5+, CD10- and were positive CYCLIN D1 expression and/or the t(11;14)(q13;q32). Eighteen patients presented a t(11;14) (q13;q32).The CYCLIN D1 negative patient had a t(11;14). Treatment history: Twenty seven patients received RiBVD in second line, 12 in third line and 10 patients after the third lines. Twenty two patients were refractory to their previous line and 27 were in relapse. Before RiBVD 44/49 patients (90%) had received high dose cytarabine, 3 Ibrutinib and 14 patients were intensified (11 at diagnosis, 3 in relapse). Efficacy: The global overall response rate (ORR) was 75% (37/49, 23 CR and 14 PR). For patients treated in 2nd line, the ORR was 85% (23/27, 16 CR and 7 PR), in 3nd line 58% (7/12, 4 CR and 3 PR), and 70% (7/10) for the others (3 CR and 4 PR). Young patients had an ORR of 64% (9/14, 8 CR, 2 RP) and elderly pts 77% (27/35, 15 CR, 12 PR). For relapsed and refractory pts the ORR was respectively 85% (23/27, 15 CR and 8 PR) and 63% (14/22 with 8 CR and 6 PR). For Classic and blastoid variants the ORR was 81.5% (31/38, 20 CR and 11 PR) and 54% (6/11, 3 CR and 3 PR) respectively. Note that 2/3 pts receiving RiBVD regimen post Ibrutinib failure, reached PR (n=2) and showed stable disease (n=1). Major toxicities were seen in 31 pts (63%) with grade 3/4 hematological toxicity in 22 pts, grade 3 neurotoxicity in 3 pts, grade 3/4 cardiotoxicity in 3 pts, grade 3/4 infectious complications in 8 pts, grade 4 fatigue in 3 pts and grade 3 digestive-tract or cutaneous toxicity in one pt each. At the update point, 17 pts had died, 15 for lymphoma progression, 2 for TRM while experiencing a CR (infectious and leukemia). The follow-up of the 32 surviving pts was 14.5 month. The median PFS was 9 months for the 49 pts. The PFS was statistically affected by the pathologic type (classic vs Blastoid, p=0.03), the number of prior treatment (one vs >one, p=0.04) and response to RiBVD (CR vs PR vs no response, p65) or the state (relapse or refractory) at the time of RiBVD had no impact on PFS. Conclusion The RiBVD regimen which shows remarkable efficacy in frontline treatment of elderly MCL pts, shows potential as a salvage therapy for refractory or relapsed MCL following cytarabine based treatment. This is particularly true for the 47% of patients achieving CR for which 2 years PFS was 71% regardless of their age. 1. Cheah CY, Seymour JF, Wang ML. Mantle Cell Lymphoma. J Clin Oncol 2016; 34: 1256-1269. 2. Gressin R, Callanan M, Daguindau N et al. Frontline therapy with the RiBVD regimen elicits high Clinical and Molecular Response Rates and long PFS in elderly patients Mantle Cell Lymphoma (MCL); Final Results of a Prospective Phase II trial by the LYSA group. Blood 2014. Disclosures No relevant conflicts of interest to declare.