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The main objective of the MCL3 study was to improve outcome for patients not in complete remission (CR) before transplant by adding (90)Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen. One hundred sixty untreated, stage II-IV mantle cell lymphoma patients

Our aim was to describe a large population-based cohort of diffuse large B-cell lymphoma (DLBCL) during the last decade, evaluating possible improvement in survival and to identify subgroups in need of novel treatment strategies. The study population encompassed all patients diagnosed with DLBCL in Sweden from 2000 through 2010. Altogether 5349 patients were identified. There was no increase in incidence for females, but for males there was an estimated yearly increase in incidence by 0.019 per 10 000. When adjusted for age and gender, the improvement in overall survival for the whole group was estimated at 4.5% per year, most prominent in the age group 60-78 years, and in patients with good performance status. In this large dataset, we were able to detect a clear improvement in overall survival in DLBCL, although restricted to specific prognostic subgroups, and to identify specific disease presentations that significantly affect overall survival.

INTRODUCTION: The addition of high-dose cytarabine to mantle cell lymphoma (MCL) treatment regimens has significantly prolonged survival of patient subgroups, but relapses are common and are usually associated with treatment resistance. High-dose cytarabine is effective due to the improved retention of ara-CTP by target cells, but likewise toxic, causing mainly hematological side effects. Thus, understanding the molecular mechanism(s) responsible for resistance and to identify predictive markers for resistance and/or sensitizing agents would be of great clinical value. In an attempt to elucidate those mechanisms and to create a tool for drug discovery investigations, we established a unique and molecularly reproducible cytarabine resistant model from the Z138 MCL cell line. Using molecular profiling, we confirm that down-regulation of the deoxycytidine kinase (dCK) protein is key to development of resistance. The MCL resistance model was carefully characterized by screening with annotated compound libraries focused on (i) chemotherapeutics to identify potential cross-resistance and/or sensitivity, and (ii) epigenetic pathways to investigate sensitivity, but also to select individual candidates for sensitization of cytarabine resistant cells. Furthermore, we investigated the hypothesis that the levels of dCK at diagnosis can be used to predict cytarabine resistance through measurement of event-free survival using the Nordic MCL 2/3 cohort, where patients are treated with a combinatorial protocol including high-dose cytarabine. MATERIAL AND METHODS: The first resistant sub-clone defined as Z138 Cytarabine Resistant (Z138-CytR) was established by continuous exposure of wild type Z138 Cytarabine Naïve Sensitive cells (Z138-CytNS) to increasing concentrations (0.005 - 0.3 µM) of cytarabine. Using this model, we could identify the approximate time to resistance development, and utilize this information for developing a novel highly reproducible time-controlled cytarabine resistant model. Molecular changes were investigated by protein and gene expression analyses. Utilizing drug libraries, the cell model was further used to identify substances with growth reducing effect on cytarabine resistant cells. RESULTS AND CONCLUSION: Gene expression profiling revealed that major transcriptional changes occur during the initial phase of adaptation to cellular growth in cytarabine containing media, and only few genes are deregulated upon development of resistance. Instead, resistance to cytarabine was shown to be mediated by down-regulation of the dCK protein, responsible for activation of nucleoside analogue prodrugs. Consequently, cytarabine resistant cells showed cross-resistance to other nucleoside analogues including gemcitabine, cladribine and fludarabine. Of major importance, using drug libraries, we identify substances with growth reducing effect on cytarabine resistant cells. Further investigations are needed to pinpoint compounds that can prevent the down-regulation, or possibly restore dCK protein levels. The possibility to predict cytarabine resistance in diagnostic samples was assessed, but analysis show that the majority of patients have moderate to high expression of dCK at diagnosis, corresponding well to the initial successful response to cytarabine-containing treatment protocols. Disclosures Geisler: Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy. Jerkeman:Celgene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Mundipharma: Research Funding.

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL) over the last 10-15 years, this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, with an overall response rate (ORR) of 68% as a single agent in the relapse situation. In vitro, ibrutinib has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. A phase I trial with this combination has been performed in 22 patients with untreated follicular lymphoma (Alliance 051103). In this trial, rash was the most common adverse event (AE), occuring in 73% of pts, with grade 3 rash in 32%. Methods: Eligibility criteria were: patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing was performed on frozen tumor cells from bone marrow at time of relapse, including the following genes: ATM, CCND1, TP53, KMT2D, NOTCH1, NOTCH2, WHSC1 and BIRC3. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment. Given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in 12 months, June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. In total, 17/50 pts have discontinued treatment (n=9 due to PD, n=4 due to AE, n=2 withdrew consent, n=1 proceeded to alloSCT and n=1 due to other cause). Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). One event of laboratory tumor lysis syndrome was reported, and two events of atrial fibrillation, without reduction or discontinuation of ibrutinib. With a median follow up time of 7 months, 29 patients were evaluable for efficacy as of July 14, 2016. The ORR to date is 83% with 12 patients achieving CR (41%) and 12 PR (41%). Median duration of response and PFS has not been reached. One of three evaluable patients with progression on single agent ibrutinib responded with a PR, with ongoing response at 9 months. Of the 13 patients evaluable for MRD at 6 months, 7/12 patients have achieved molecular remission in blood and 7/13 in bone marrow. Conclusions: So far, the combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in patients with R/R MCL, associated with molecular remission. Cutaneous toxicity was manageable, in contrast to what has been reported with a similar combination in untreated patients with follicular lymphoma. Up-dated results will be presented at the annual meeting, including data on mutational profile as biomarker for efficacy. This trial was registered at http://clinicaltrials.gov as NCT02460276. Disclosures Jerkeman: Gilead: Research Funding; Mundipharma: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Niemann:Abbvie: Research Funding; Roche: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Geisler:Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy.

Background: Minimal residual disease monitoring has been shown to be of relevance in mantle cell lymphoma (MCL) to evaluate quality of remission and predict clinical relapse. The main objectives of the present study were to determine the value of minimal residual disease (MRD) monitoring to guide pre-emptive treatment with rituximab, and to predict clinical relapse in MCL following autologous stem cell transplantation (ASCT) in two prospective trials (MCL2 and MCL3) with long-term follow-up conducted by the Nordic Lymphoma Group. Methods: Patients treated in the two studies received a total of 6 alternating cycles with R-CHOP and R-Ara-C followed by a peripheral blood stem cell harvest and high-dose therapy with ASCT. Additionally, responding patients not in CR before ASCT in the MCL3 trial received yttium-90 ibritumomab tiuxetan (0.4 mCi/kg) as intensification one week prior to the standard conditioning with BEAM/C. Staging included physical examination, blood tests, computed tomography (CT) scans and bone marrow (BM) aspiration and biopsy. Clinical and molecular response evaluation was repeated 2-3 months and 6 months after transplant, and then every 6 months until relapse or 5 years follow-up. A combined standard nested and quantitative real-time PCR assay was used to estimate MRD involvement in consecutive post-transplant BM/PB samples. Molecular relapse after ASCT was defined as; 1. Conversion from standard nested PCR negative to standard nested PCR positive, or 2. For patients who were MRD positive post-ASCT, a significant (>5 fold) increase of the real time quantitative PCR detectable MRD level in two consecutive BM samples. Patients in clinical remission who developed a molecular relapse in both studies received 4 weekly doses of rituximab (375 mg/m2). This treatment could be repeated in case of recurrent molecular relapses. Results: An MRD marker for Bcl-1 or IgH rearrangement was obtained for 94 out of 160 patients (59%) recruited in the Nordic MCL2 trial, and for 121 out of 160 (76%) in the consecutive MCL3 trial. 183 patients, who had completed induction therapy and autologous stem cell transplantation (ASCT) in the two studies and where a PCR marker in blood or bone marrow was obtained, were included in the current analysis. Median follow-up from inclusion was 8.5 years among survivors. Patients who were MRD negative post-ASCT had significantly longer relapse-free survival (RFS) and overall survival (OS) compared to those who were MRD positive (P Conclusion: We observed a continuous pattern of MRD relapses that did not subside even after 5-10 years and included all risk groups. Hence, it is fair to consider MCL as a chronic incurable lymphoma entity and novel approaches will be necessary to change the natural course of this disease. Detection of MRD was shown to be a predictor for clinical relapse and inferior survival. Additionally, the data strongly suggests that pre-emptive rituximab treatment delayed clinical relapse in MCL. We recommend MRD monitoring post-ASCT in MCL as a useful approach to select the MRD positive patients for novel strategies in future trials and as an alternative to maintenance therapy for all patients. The MCL2 and MCL3 trials were registered at www.isrctn.com as ISRCTN 87866680 and at www.clinicaltrials.gov as NTC 00514475, respectively. Disclosures Kolstad: Nordic Nanovector: Other: Membership of Scientific Advisory Board. Jerkeman:Janssen: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Mundipharma: Research Funding; Gilead: Research Funding. Geisler:Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy.

Background: Peripheral T-cell lymphomas (PTCLs) comprise a group of non-Hodgkin lymphomas (NHLs) of mature T-cell origin with generally aggressive clinical behavior. Most systemic PTCLs are treated with anthracycline-based combination chemotherapy; however, outcomes remain relatively poor for most subtypes except ALK-positive anaplastic large cell lymphoma (ALCL). We have used landmark analyses based on event-free survival (EFS) to identify clinically useful endpoints in B-cell NHLs, with EFS at 24 (EFS24) months identified to stratify overall survival (OS) in aggressive B-cell NHL. Here we examined the ability of EFS24 to predict subsequent OS in a large, multinational PTCL cohort. Methods: A cohort of newly diagnosed PTCL patients treated with curative intent combination chemotherapy regimens was assembled from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), Swedish Lymphoma Registry (SWE), and British Columbia Cancer Agency (BCCA). Subtypes included ALK-negative ALCL, angioimmunoblastic T-cell lymphoma (AITL), PTCL, not otherwise specified (NOS), enteropathy-associated T-cell lymphoma (EATL), extranodal NK/T-cell lymphoma, nasal type (ENKTL), and hepatosplenic T-cell lymphoma (HSTCL). Patients were followed based on local institution guidelines, and EFS was defined as time from the date of pathologic diagnosis to progression, re-treatment, or death due to any cause. EFS24 was defined as being alive and event-free 24 months from diagnosis. Subsequent OS was defined as time from achieving EFS24 (24 months from diagnosis) or time from progression in patients failing to achieve EFS24 (progression within 24 months of diagnosis). OS was compared to the age-, sex-, and country-matched general population using United States, Sweden, and British Columbia rate tables via standardized mortality ratios (SMR) and expected survival. Results: 775 patients diagnosed from 2000-2012 were included in the combined analysis with diagnosis by the WHO classification at the respective institutions (MER=138, SWE=422, BCCA=215). Median age at diagnosis was 64 years (range 18-89) and 63% were male. Patient characteristics are summarized in the table. 736 (95%) received anthracyline-based therapy at diagnosis. At a median follow-up of 77 months (range 1-185), 516 patients (67%) had died. The percentage of patients achieving EFS24 was similar across the 3 cohorts (MER=39%, SWE=35%, BCCA= 36%, combined=36%). Median survival after progression within the first 24 months was only 4.9 months (95% CI: 3.8-5.9), with a 5-year OS of 11% and SMR of 46.4 (95% CI: 41.8-51.3). In contrast, median survival after achieving EFS24 was not reached, with a 5-year OS of 78% (95% CI: 73%-84%). This was inferior to the expected survival of 92% in the age-, sex-, and country matched population (SMR=3.16; 95% CI: 2.48-3.98). In EFS24 subgroup analyses, more favorable outcomes were observed in younger patients (age Conclusions: Assessment of EFS24 stratifies subsequent outcome in PTCL. Patients with early relapse from PTCL have extremely poor outcomes. However, over one-third of patients with PTCL remain in remission two years from diagnosis after initial chemotherapy and have encouraging OS rates, although survival remains significantly worse than the matched general population. Subset analysis suggests that younger patients and patients who receive autologous stem-cell transplant in first CR have 5-year survival rates that approach 90%, though still below the expected survival of the background population. The marked differences in OS after failing or achieving EFS24 in PTCL patients suggest that this endpoint may be useful for patient counseling, as a clinical trial endpoint, and as an endpoint to assess novel biomarkers for risk stratification. Table Table. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Maurer: Celgene: Research Funding; Kite Pharma: Research Funding. Jerkeman:Mundipharma: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Celgene: Research Funding. Connors:Seattle Genetics: Research Funding; Millennium Takeda: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Introduction: Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of early central nervous system (CNS) progression is high. Here we present the final results from a Nordic phase II study, where dose-dense chemoimmunotherapy including early systemic CNS prophylaxis with high dose methotrexate (HD-Mtx), further intensified by intrathecally (IT) administered liposomal cytosine arabinoside (AraC), was given. Patients and methods: Inclusion criteria were age 18-65 years, de novo DLBCL or grade 3B follicular lymphoma without clinical, radiological or cytological signs of CNS involvement, age adjusted IPI 2-3, WHO performance score 0-3, and/or anatomical sites related to increased risk for CNS recurrence (e.g. testis, facial sinuses, orbita). Treatment consisted of two courses of HD-Mtx in combination with R-CHOP14, followed by four courses of R-CHOEP14 and one course of R-HD-AraC. Liposomal AraC was administered IT at courses 1, 3 and 5 (omitted during a period of production halt). Primary end points were failure free survival (FFS; disease progression, discontinuation of protocolled therapy due to toxicity, death from any cause) and CNS progression rate at 18 months. Among the secondary endpoints were the identification of biological risk factors for high risk disease and prognostic role of cerebrospinal fluid (CSF) cytology-/flow cytometry (FC)+for CNS recurrence. Results: Of the accrued 143 patients, 140 met the inclusion criteria and were evaluable for baseline characteristics and primary endpoints. Of these, 132 had a complete set of treatment data. The male/female ratio was 1.7 and the median age 56 years (range 20-64). The majority of the patients had DLBCL (96%), advanced clinical stage (93%), elevated LDH (91%), more than one extranodal site (73%), and B-symptoms (64%). A bulky lesion (>10 cm) was present in 37% of the patients and 11 CSF samples (8%) were FC+. Most patients (n=127, 96%) received a full treatment schedule. Liposomal AraC was given to 81 (61%) and radiotherapy to 39 (30%) patients. Grade 4 infections were observed in 12% of the patients. The frequency of grade 3-4 mucositis as well as gastrointestinal toxicity was 20%, and of grade 3 arachnoiditis 2,5%. Three toxic deaths were observed. In addition, three patients developed AML/MDS and one PML. At the end of treatment, CR/CRu, PR and PD rates were 79%, 17% and 3%, respectively. Of the 120 patients who underwent PET-CT, 92 (77%) achieved a metabolic CR (Deauville score (DS) 1-3). Three patients had primary refractory disease. At a median follow-up of 30 months, additional 14 patients had relapsed, three of them in the CNS (only one had a pre-therapeutic FC+ CSF), and 15 had died. FFS, PFS, OS and CNS progression rates at 30 months were 80%, 83%, 90%, and 2.4%, respectively. PET positivity (DS 4-5) at the end of treatment (p=0.019) and BCL2 expression (p=0.049) were associated with increased risk of progression, whereas other factors, such as molecular subtype (GC versus non-GC), Ki-67 score (≥70%), aaIPI group (2 versus 3), number of extranodal sites, FC-based CSF positivity, and treatment with liposomal AraC did not seem to have significant impact on outcome. Conclusions: Safety profile and final outcome results of the Nordic CHIC trial indicate high response rates, favorable survival, low number of CNS recurrences and manageable toxicity as a result of this CNS targeted intensive therapy schedule. PET response at the end of therapy and selected biological factors identify patients at high risk of progression. Disclosures Leppa: Roche: Honoraria, Other: Travel expenses, Research Funding; Janssen: Research Funding; Bayer: Research Funding; Mundipharma: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Other: Travel expenses; CTI Life Sciences: Honoraria; Merck: Other: Travel expenses. Joergensen:Amgen: Research Funding; Mundipharma: Research Funding. Mannisto:SOBI: Honoraria; Pfizer: Honoraria; Gilead: Other: Travel expenses; Celgene: Other: Travel expenses; Novartis: Other: Travel expenses; Amgen: Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Roche: Honoraria, Other: Travel expenses. Jerkeman:Gilead: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Holte:Amgen: Research Funding; Mundipharma: Research Funding.

INTRODUCTION: During the past decades, the outcome of Mantle Cell Lymphoma (MCL) treatment has improved substantially in younger patients. In a recent update of the Nordic MCL2 trial we show very long response durations after a median follow-up of 11.4 years, but we also observe a continuous pattern of relapses even after 10 years of remission.(Eskelund et al, 2016) The course of this disease remains very heterogeneous, and with the current prognostic indexes we are unable to identify patients who might be cured by the current standard-of-care and others who would possibly benefit from alternative frontline approaches. Recently, next-generation sequencing (NGS) studies have explored the mutational landscape of MCL, however, in inhomogeneous and diversely treated cohorts or with short follow-up. Still, TP53 and NOTCH1/2 mutations have been shown to be prognostic markers. In our current study we examine the prognostic impact of aberrations in the most frequently mutated genes in MCL in a homogenously and optimally treated patient cohort, with a long-term follow-up. MATERIAL AND METHODS: Freshly frozen DNA from diagnostic bone marrow samples from patients included in two prospective Nordic trials, MCL2 and MCL3 were analysed. In both trials patients received intensified first line induction therapy with alternating courses of R-CHOP and R-HD-Cytarabine and consolidation with high-dose therapy and ASCT. All patients signed an informed consent.(Geisler et al, 2008; Kolstad et al, 2014). NGS was performed using the Ion Torrent Technology. A targeted panel of 8 genes frequently mutated in MCL was constructed on the basis of previous NGS studies.(Bea et al, 2013; Zhang et al, 2014) The panel included all coding regions of the following genes: ATM, CCND1, TP53, KMT2D, NOTCH1, NOTCH2, WHSC1 and BIRC3. Cut-off for calling a mutation was set to a variant allele frequency >3%. Mean depth was >1500X in all patients. RESULTS: So far, we have mutational data from 72 patients. Patients were previously untreated and Of the 72 patients, mutations were detected in 33 cases. Twenty-one patients carried 1 mutation and 12 patients had >1 mutation (2-4). Mutations were distributed as follows: ATM 15 (21%), KMT2D 11 (15%), WHSC1 7 (10%), TP53 6 (8%), CCND1 5 (7%), NOTCH2 4 (6%), NOTCH1 3 (4%), BIRC3 2 (3%). In univariate analyses, mutations in TP53 were highly predictive of an inferior outcome (median OS and PFS were 14 and 10 months, respectively; p1 mutations. In multivariate analyses, the only prognostic significant mutations were TP53 (p TP53 mutations were associated with increased Ki67 expression, median 30% (range 20-80%), higher risk MIPI/MIPI-B/MIPI-C, and 4 out of 6 patients had blastoid morphology at diagnosis. All 6 TP53 mutations were found in the DNA-binding domain, and 5 were missense mutations while the last was a frameshift mutation. Patients with missense mutations all died within 3 years (range 6-34 months) due to relapsing or progressive disease, while PFS and OS of the latter patient was 4.6 years and 8.4 years, respectively. We found no predictors for late relapses. CONCLUSION: Here we evaluate the prognostic impact of mutations in eight genes that are commonly involved in MCL in a cohort of 72 younger patients who received intensified induction therapy and ASCT in the Nordic MCL2 trial. In line with previous reports, we demonstrate a negative prognostic impact of TP53 and NOTCH1/2 mutations; however, in multivariate analyses only TP53 and NOTCH1 mutations held significance. Missense mutations in the DNA binding domain of TP53 seem to predict an exceedingly poor short term outcome. At the annual meeting, we will present mutational analyses and long term follow up of >150 patients from the combined MCL2 and MCL3 cohort. Disclosures Jerkeman: Amgen: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding. Geisler:Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy.

This study was conducted to explore treatment and disease-related effects on health-related quality of life (HRQoL) in patients with aggressive lymphoma, to identify predictors for impaired long-term HRQoL, and to analyze the prognostic value of pretreatment HRQoL. Ninety-five patients with aggressive lymphoma, constituting a subset of a randomized multicenter trial comparing CHOP and MACOP-B, entered a HRQoL study, using the EORTC QLQ-C30 questionnaire. Patient scores were compared to scores from an age- and gender-adjusted reference population sample, and evaluation of the prognostic value of pretreatment QoL scores in relation to clinical prognostic factors was performed. Before treatment, patients exhibited lower scores of global QoL, physical, role, and social functions, and more appetite loss, compared to the reference population. Role functioning improved compared to baseline, but remained depressed compared to the reference group more than 8 mo after end of treatment. By then, the patient group displayed no difference in other HRQoL variables compared to that of the reference population. No reliable predictor for impaired long-term HRQoL could be identified. In multivariate analysis, including the factors of the International Prognostic Index, pretreatment global QoL was an independent prognostic marker for overall survival. In conclusion, in this population with aggressive lymphoma and favorable prognostic features, HRQoL was not substantially affected during the first year after diagnosis. Pretreatment global QoL may constitute a significant prognostic factor, meriting further investigation in prospective studies.

In patients with intermediate or high grade non-Hodgkin lymphoma (NHL), third generation chemotherapy regimens have been introduced to improve survival in comparison with the standard CHOP regimen. However, most studies have found no difference between these two treatments. We conducted a meta-analysis to assess the effectiveness of third generation regimens as compared with CHOP. Our study included the randomized controlled trials published in English from 1970 to 1999. After a Medline search, 5 trials were found to meet our inclusion criteria. A total of 1982 patients, that were enrolled in these trials, were included in the survival meta-analysis. Our methodology retrieved patient-level information from all of these subjects; survival up to 9 years after randomization was compared between the two treatment options. The results of our meta-analysis showed that, in comparison with CHOP, third generation chemotherapy did not prolong survival at levels of statistical significance (chi-square by log-rank test = 1.44, P = 0.23). The relative death risk for third generation regimens vs. CHOP was 0.92 (95%CI: 0.80 to 1.06;P = 0.26). We conclude that, on the basis of our meta-analysis, third generation regimens do not confer any survival benefit to patients with intermediate or high grade NHL as compared with CHOP. © 2001 Cancer Research Campaign http://www.bjcancer.com

Summary Background: The long-term survival of patients with advanced stage aggressive lymphoma has not improved significantly during the last twenty years. In a randomised trial, the efficacy of MACOP-B, a six-drug weekly chemotherapy regimen, was compared to CHOP, the current standard regimen, in terms of overall and failure-free survival, toxicity and health related quality of life. Patients and methods: Four hundred five patients with aggressive lymphoma, stage II—IV, age 18-67, were randomised to receive either 12 weeks of MACOP-B or 8 courses of CHOP over 24 weeks. Special emphasis was put in the definition of Ann Arbor stage in extranodal disease. A subset of 95 patients also entered a quality of life study, based on the EORTC QLQ- C30. Results: Thirty-one patients were ineligible. Among the remaining 374 patients, the median age was 52 years. Accord- ing to the age-adjusted International Prognostic Index, 37% were 'high-intermediate' or 'high-risk' patients. No difference could be demonstrated, either in overall survival (60% at five years in the MACOP-B group and 59% in the CHOP group) or in failure-free survival (47% at five years with MACOP-B and 44% with CHOP). In terms of quality of life, physical function and global quality of life were more impaired in patients receiving MACOP-B, who also exhibited more non-haemato- logical toxicity. Conclusion: No superiority of MACOP-B compared to CHOP could be demonstrated. CHOP remains the treat- ment of choice in low-risk patients. At present, intensified or experimental treatment should be reserved for high-risk disease.

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment-related morbidity, additional parameters need to be evaluated to enable risk-adapted treatment selection. We have investigated the individual prognostic role of the MIPI and molecular markers including SOX11, TP53 (p53), MKI67 (Ki-67) and CCND1 (cyclin D1). Furthermore, we explored the possibility of creating an improved prognostic tool by combining the MIPI with information on molecular markers. SOX11 was shown to significantly add prognostic information to the MIPI, but in multivariate analysis TP53 was the only significant independent molecular marker. Based on these findings, we propose that TP53 and SOX11 should routinely be assessed and that a combined TP53/MIPI score may be used to guide treatment decisions.

Background: Many patients with aggressive B-cell lymphomas and high clinical risk score still die of lymphoma after conventional R-CHOP chemoimmunotherapy. We hypothesized that intensified chemoimmunotherapy including systemic central nervous system (CNS) prophylaxis improves outcome and reduces the incidence of CNS-related events. Patients and methods: Inclusion criteria were age 18-65 years, primary diffuse large B-cell lymphoma or grade III follicular lymphoma without clinical signs of CNS disease and negative cerebrospinal fluid cytology, age-adjusted International Prognostic Index 2-3 and WHO performance score 0-3. Treatment consisted of six courses of R-CHOEP-14 followed by a course of high-dose cytarabine and a course of high-dose methotrexate. Primary end point was failure-free survival (FFS) at 3 years. Results: A total of 156 eligible patients with a median age of 54 years (range 20-64) were included. Three toxic deaths were observed. Three-year overall survival (OS) and FFS rates (median observation time 52 months for survivors) were 81% and 65%, respectively. Seven patients experienced CNS relapse, all within 6 months. Conclusions: The results are promising with favorable 3-year OS and FFS rates, a low toxic death rate and a lower than expected number of CNS events. CNS progression might be further reduced by earlier CNS prophylaxis. CinicalTrials.gov.identifier: NCT01502982.

Plasma immunoprofiling of patients with high-risk diffuse large B-cell lymphoma: a Nordic Lymphoma Group study

Background The transcription factor SOX11 is of diagnostic and prognostic importance in mantle cell lymphoma (MCL) and epithelial ovarian cancer (EOC), respectively. Thus, there is an unmet clinical and experimental need for SOX11-targeting assays with low background, high specificity and robust performance in multiple applications, including immunohistochemistry (IHC-P) and flow cytometry, which until now has been lacking. Methods We have developed SOX11-C1, a monoclonal mouse antibody targeting SOX11, and successfully evaluated its performance in western blots (WB), IHC-P, fluorescence microscopy and flow cytometry. Results We confirm the importance of SOX11 as a diagnostic antigen in MCL as 100% of tissue micro array (TMA) cases show bright nuclear staining, using the SOX11-C1 antibody in IHC-P. We also show that previous reports of weak SOX11 immunostaining in a fraction of hairy cell leukemias (HCL) are not confirmed using SOX11-C1, which is consistent with the lack of transcription. Thus, high sensitivity and improved specificity are demonstrated using the monoclonal SOX11-C1 antibody. Furthermore, we show for the first time that flow cytometry can be used to separate SOX11 positive and negative cell lines and primary tumors. Of note, SOX11-C1 shows no nonspecific binding to primary B or T cells in blood and thus, can be used for analysis of B and T cell lymphomas from complex clinical samples. Dilution experiments showed that low frequencies of malignant cells (~1%) are detectable above background using SOX11 as a discriminant antigen in flow cytometry. Conclusions The novel monoclonal SOX11-specific antibody offers high sensitivity and improved specificity in IHC-P based detection of MCL and its expanded use in flow cytometry analysis of blood and tissue samples may allow a convenient approach to early diagnosis and follow-up of MCL patients.

Objectives To determine whether serum vascular endothelial growth factor (s-VEGF) levels and VEGF gene expression in tumor tissue predict survival of diffuse large B-cell lymphoma (DLBCL) patients treated with chemoimmunotherapy. Methods VEGF levels were measured in serum samples from 102 patients

Introduction MCL is an incurable aggressive B-cell lymphoma with a poor overall prognosis. For patients with MCL who fail initial therapy (ie, with relapsed or refractory [R/R] disease), treatment options historically have been limited. While remission duration is generally short, the goal of therapy has been to achieve remission while balancing treatment-related toxicities. Consequently, a substantial proportion of patients continuously suffer from lymphoma symptoms and other disease signs, such as itching and trouble sleeping or concentrating. Additionally, worries and high emotional sensitivity lead to reduced functional status and well-being. Therefore, it is crucial to any treatment to maintain and improve the functional status and well-being of patients with R/R MCL for as long as possible throughout the treatment period. Methods RAY (MCL3001) is a phase 3, randomized, open-label, multicenter study in patients with R/R MCL. Patients were randomized in a 1:1 ratio to receive ibrutinib (560 mg once daily) or temsirolimus (175 mg on days 1, 8, and 15 of Cycle 1; 75 mg on days 1, 8, and 15 of subsequent cycles). Stratification factors were the number of prior lines of therapy (1-2 vs ³3) and simplified MCL international prognostic index risk (low [0-3] vs intermediate [4-5] vs high [6-11]). Patients in both arms received treatment until disease progression or unacceptable toxicity. Primary end point of the study was progression-free survival (PFS), as assessed by an independent review committee. Lymphoma symptoms were assessed using the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) questionnaire lymphoma subscale. The FACT-Lym was administered before any tests, procedures, or other consultations, and was used until disease progression, death, or the clinical cutoff, whichever came first. Median time to worsening (TTW), a prespecified secondary end point, and time to clinically meaningful improvement (TTI) on the lymphoma subscale were estimated. Worsening was defined as a ≥ 5-point decrease from baseline and clinically meaningful improvement as a ≥ 5-point increase from baseline. TTW and TTI on the lymphoma subscale were examined using Kaplan-Meier methods. Results In total, 280 patients were randomized to ibrutinib (n = 139) or temsirolimus (n = 141); 253 patients (ibrutinib, n = 130; temsirolimus, n = 123) provided FACT-Lym lymphoma subscale responses at baseline. Patients were compliant to therapy, and attrition was balanced between treatment arms. Disease characteristics and demographics at baseline (including FACT-Lym lymphoma subscale scores) were also generally well balanced. The study met its primary end point with a statistically significant 57% reduction in disease progression or death (PFS) with ibrutinib versus temsirolimus (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.32-0.58; p < 0.0001). The median PFS was 14.6 months for the ibrutinib arm and 6.2 months for the temsirolimus arm. When adjusted for exposure, incidence of TEAEs was lower for the ibrutinib arm than the temsirolimus arm. The proportion of patients with worsening from baseline on the FACT-Lym lymphoma subscale was lower for ibrutinib compared with temsirolimus (26.6% vs 51.8%, respectively). Median TTW was not reached with ibrutinib versus 9.7 weeks with temsirolimus, with a statistically significant reduction in the risk of worsening of 73% (p < 0.0001; Figure 1). The proportion of patients with a clinically meaningful improvement from baseline on the FACT-Lym lymphoma subscale was higher for ibrutinib compared with temsirolimus (61.9% vs 35.5%, respectively). Median TTI was shorter for ibrutinib compared with temsirolimus (6.3 weeks vs 57.3 weeks, respectively; HR, 2.19; p < 0.0001; Figure 2). Conclusions RAY (MCL3001) is the first trial comparing different targeted approaches in R/R MCL. The presented data indicate that ibrutinib is associated with greater improvements and less worsening in lymphoma symptoms compared with temsirolimus, as measured by the lymphoma subscale of the FACT-Lym. These results suggest that the superior efficacy results and favorable safety profile of ibrutinib are accompanied by better lymphoma symptom outcomes, indicating significant clinical benefit for the majority of patients with R/R MCL. Disclosures Hess: Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, Celgene, Novartis: Consultancy. Rule:J&J: Consultancy, Other: Travel reimbursement, Research Funding; Roche: Consultancy, Other: Travel reimbursement; Celgene: Consultancy, Other: Travel reimbursement; Gilead: Research Funding. Jurczak:CELLTRION, Inc,: Research Funding. Rusconi:Roche: Honoraria. Witzens-Harig:Pfizer: Honoraria, Research Funding; Roche: Honoraria. Bandyopadhyay:Janssen: Employment. Goldberg:Janssen: Employment. Bothos:Janssen: Employment. Enny:Janssen: Employment. Vermeulen:Janssen: Employment. Traina:Janssen: Employment.

Introduction In comparison to aggressive NHL, CNS involvement is exceedingly rare in patients (pts) with Hodgkin lymphoma (HL). Thus, the clinical features and outcomes are not well described. Patients and Methods For this international retrospective analysis, institutional (n =4), national (n =2) and cooperative group (n =1) databases were reviewed for pts with classical HL who developed histologically proven CNS involvement at any stage during their disease course. We included pts diagnosed with CNS involvement after January 1, 1995 and collected clinicopathological characteristics (at both initial diagnosis and at time of CNS involvement), treatment details and outcomes. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method from date of CNS involvement to date of disease progression or death from any cause and death from any cause, respectively. Results We screened 32,047 patients with classical HL in our combined databases and identified 18 pts with histologically confirmed CNS lymphoma, with an estimated crude incidence of 0.05%. These pts had a median age of 40 (range 20 - 84) years at the time of diagnosis of CNS involvement. The characteristics at the time of initial diagnosis of HL are summarized in table 1. CNS involvement was present at the time of initial diagnosis in 10 pts (56%) of whom 3 had isolated CNS involvement and 5 had concurrent systemic involvement (details were unavailable in 2 pts). CNS HL was a feature of relapsed/refractory disease in 8 (44%), 7 of whom had concurrent systemic involvement. The most common presenting symptoms were pyramidal weakness (n=7, 39%), headache (n=5, 28%), sensory change (n=4, 22%) and confusion (n=3, 17%). Lesions were parenchymal (n=10, 62%), leptomeningeal (n=2, 12%) or both (n=4, 25%). The median number of discrete CNS lesions detected by imaging was 1 (range 0 - >10), which affected cortical (n=9, 50%) or subcortical structures (n=6, 33%) and the spinal cord (n=2, 11%). The disease appeared to arise from the dura in 9 cases (50%), and the median size of the largest lesion was 2.5 cm (range 1 - 6). Cerebrospinal fluid (CSF) analysis was performed in 10 (56%) pts; of these, cytology was positive in 4 cases with a median CSF white cell count of 10/uL (range 0 - 136). CSF protein was elevated in 7 cases. Immunohistochemistry for Epstein-Barr virus RNA was done on 6 CNS biopsies, of which 3 were positive. Information regarding therapy was available in 15 pts; 9 received radiotherapy (alone (n=4), with steroids (n=1), with systemic (n=2) or intrathecal chemotherapy (n=2)). A further 3 pts were treated with systemic therapy (alternating cycles of R-IVAC/MTX (n=1), brentuximab vedotin (n=1), MTX, cytarabine and thiotepa (n=1), 2 with steroids alone and 1 with surgical resection alone. Of 13 pts formally evaluated for response, 7 (54%) achieved complete and 1 (8%) partial response, for an overall response rate of 62%. 1 patient underwent consolidative autologous stem cell transplantation. After a median follow up of 3.6 (range 0.8 - 13.2) years from diagnosis of CNS involvement, 9 pts experienced disease progression: 1 in the CNS alone, 3 at systemic sites alone, and 5 with both systemic and CNS sites with a median PFS of 9.5 months (Fig 1A). At last follow up, 11 pts have died (6 of progressive disease, 3 from sepsis and 2 from unknown causes) with a median OS of 37 months (Fig 1B). CNS involvement at initial diagnosis vs at relapse (Fig 1C,D) was associated with favorable PFS and OS, whilst isolated CNS involvement was associated with superior PFS but not OS (Fig 1E,F). Conclusion CNS involvement in HL is exceedingly rare and has a distinct clinical presentation with predilection for parenchymal lesions with dural extension (as opposed to true hematogenous spread), providing an important differential diagnosis for meningioma in this setting. CNS HL presenting as an initial manifestation of disease appears to be associated with favorable outcomes. Table 1. Characteristics of patients at initial diagnosis of HL Characteristics at initial diagnosis of HL data avail. n (%) Male 18 11 (61) Histologic subtype 17 Nodular-sclerosing 13 (77) Lymphocyte-rich 3 (18) Lymphocyte-depleted 1 (6) Stage 18 1 2 (11) 2 5 (28) 3 3 (17) 4 8 (44) B sx 18 10 (56) Pruritus 15 3 (20) Nodal size >10 cm 14 3 (21) Hb 15 x 109/L 13 2 (15) lymphocytes Figure 1. Figure 1. Disclosures Vose: Seattle Genetics, Inc.: Honoraria, Research Funding. Villa:Roche: Research Funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding.

Rationale: The anticonvulsant valproate is an HDAC inhibitor, which has in vitro been shown to sensitize lymphoma cell lines for CHOP chemotherapy, and to upregulate CD20 expression. Based on these findings, we initiated a dose finding trial of valproate in combination with R-CHOP in primary treatment of diffuse large B-cell lymphoma (DLBCL), including a dose expansion cohort. Methods: Eligibility criteria were: age 18-80 years, histologically confirmed (according to the WHO classification) diffuse large B-cell lymphoma stage II-IV, WHO performance status 0-2. R-CHOP was given at standard dose in 14 or 21 day cycles, 6 cycles. Valproate was given in escalating doses days 1-3, starting at 10 mg/kg every 8 hrs, by a standard 3+3 design. Prednisone was given days 1-5, R-CHOP on day 3. Response was evaluated according to the Lugano criteria. Results: In the phase I portion, the MTD of valproate was established as 20 mg/kg every 8 hrs (total 60 mg/kg). At a dose of 80 mg/kg, 2 of 3 patients experienced tinnitus (grade 1 and 2) during the latter part of the treatment course. At a dose of 100 mg/kg, 1 of 5 patients developed hearing impairment, grade 1, after 3 cycles, which worsened to grade 2 after 4 cycles, leading to omission of valproate. By August 1, 2015, 28 patients have been included, of which 17 in the dose finding portion. The median age is 69 years (range 47-78). According to the IPI, 43, 36 and 21% were low, low-intermediate and high intermediate/high risk, respectively. Apart from the auditory adverse effects presented above, toxicity was comparable to that of standard R-CHOP, without any impact on hematological toxicity. Presently, 17 patients are evaluable for response after 6 cycles VR-CHOP, ORR 17/17 CR 15/17 (88%). After a median time of follow-up of 16 months, median PFS has not been reached, and estimated PFS at 18 months is 77%. One patient has died due to progressive lymphoma, 21 months after inclusion. By flow cytometry of fine needle aspirates from lymphoma lesions before and after 3 days of valproate, we could show significant upregulation of CD20 expression in 3 patients. Conclusions: Sensitization to rituximab and CHOP by pretreatment with an HDAC inhibitor is a novel therapeutic strategy for the treatment of DLBCL. At a dose of 60 mg/kg, divided into 3 doses, the combination of valproate with R-CHOP is feasible in 1st line treatment of DLBCL. Higher doses of valproate was associated with intolerable auditory side effects. Early data show promising efficacy, which may form the basis for a randomized phase III trial. The long-term efficacy of this regimen remains to be established by longer follow-up. Disclosures Drott: Respiratorius: Membership on an entity's Board of Directors or advisory committees. Relander:Respiratorius: Patents & Royalties: valproate for DLBCL. Drott:Respiratorius: Employment. Off Label Use: Valproate for treatment of diffuse large B-cell lymphoma..

Introduction MCL is an aggressive B-cell lymphoma with a poor overall prognosis. For patients who fail initial therapy, conventional chemotherapy achieves only short-term remissions. Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase that has been shown to be highly active for previously treated MCL patients (overall response rate [ORR] ~65%; complete response [CR] ~20%) in single-arm phase 2 studies. Temsirolimus has demonstrated significantly longer progression-free survival (PFS) vs investigator's choice. In this phase 3, randomized, open-label study (MCL3001 [RAY]), ibrutinib was compared with temsirolimus in patients with relapsed or refractory (R/R) MCL who had received ≥1 prior rituximab-containing therapy. Methods Patients were randomized at a 1:1 ratio to receive oral ibrutinib (560 mg once-daily) or intravenous temsirolimus (175 mg: Days 1, 8, and 15 of Cycle 1; 75 mg: Days 1, 8, and 15 of subsequent cycles). Stratification factors were number of prior lines of therapy (1-2 vs ³3) and simplified MCL international prognostic index (sMIPI) risk (low [0-3] vs intermediate [4-5] vs high [6-11]). Patients in both arms received treatment until disease progression or unacceptable toxicity. Primary end point of the study was PFS, as assessed by an independent review committee (IRC). Secondary end points included ORR, overall survival (OS), time to next treatment (TTNT), time to worsening of lymphoma symptoms (measured by FACT-Lym lymphoma subscale), and safety. Results Overall, 280 patients were randomized to ibrutinib (n = 139) or temsirolimus (n = 141). Baseline disease characteristics and demographics were generally well balanced. Median age (range) was 68 years (34-88) and median number (range) of prior lines of therapy was 2 (1-9). Approximately two-thirds of the patients had intermediate- or high-risk disease. At the time of this analysis, median follow-up was 20.0 months. Ibrutinib was superior to temsirolimus for the primary end point of IRC-assessed PFS, with a statistically significant 57% reduction in the risk of progression or death (Figure 1). The median PFS was 14.6 months for the ibrutinib arm and 6.2 months for the temsirolimus arm, respectively. At a landmark of 2 years, the PFS rate is 41% in the ibrutinib arm vs 7% in the temsirolimus arm. PFS results were consistent across most assessed subgroups. Investigator-assessed PFS was consistent with the IRC results. IRC-assessed ORR was significantly higher for ibrutinib vs temsirolimus (71.9% vs 40.4%; p < 0.0001) with a CR rate of 18.7% vs 1.4%, respectively. Median OS was not reached with ibrutinib vs 21.3 months with temsirolimus, showing a positive trend toward patients in the ibrutinib arm (reduced risk of death by 24% [HR, 0.76; 95% CI, 0.53-1.09]). However, these results may have been confounded by 23% of patients that initially received temsirolimus crossing over to receive ibrutinib. A greater proportion of patients treated with ibrutinib vs temsirolimus avoided worsening of lymphoma symptoms throughout the study; 27% of ibrutinib patients had worsening vs 52% of temsirolimus patients. Median TTNT was not reached with ibrutinib vs 11.6 months with temsirolimus. Median treatment duration was 14.4 months for ibrutinib and 3.0 months for temsirolimus. Overall, 6.5% of subjects discontinued treatment due to AEs in the ibrutinib arm and 25.5% of subjects discontinued treatment due to AEs in the temsirolimus arm. The most common TEAEs with ibrutinib were diarrhea, fatigue, and cough, whereas with temsirolimus, thrombocytopenia, anemia, and diarrhea were most commonly observed (Table 1). Grade ³3 TEAEs were reported for 67.6% of ibrutinib patients vs 87.1% of temsirolimus patients; most frequent were thrombocytopenia, anemia, and neutropenia. When adjusted for exposure, TEAE incidence was consistently lower for the ibrutinib arm vs the temsirolimus arm. Conclusions Ibrutinib is superior to temsirolimus for PFS and ORR, and showed preferable tolerability. The results of this phase 3 trial confirm the efficacy and favorable safety profile of ibrutinib shown in phase 2 studies. Future concepts will investigate ibrutinib-based combination approaches for patients with R/R MCL. Disclosures Rule: Gilead: Research Funding; Celgene: Consultancy, Other: Travel reimbursement; J&J: Consultancy, Other: Travel reimbursement, Research Funding; Roche: Consultancy, Other: Travel reimbursement. Rusconi:Roche: Honoraria. Joao:Celgene, Novartis: Consultancy; Janssen, Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Honoraria, Research Funding; Roche: Honoraria. Hess:Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Balasubramanian:Janssen: Employment, Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Bandyopadhyay:Janssen: Employment. Sun:Janssen/J&J: Employment, Equity Ownership. Goldberg:Janssen: Employment. Bothos:Janssen: Employment. Traina:Janssen: Employment. Enny:Janssen: Employment. Rizo:Janssen: Employment. Vermeulen:Janssen: Employment.

Introduction: The transcription factor SOX11 is normally expressed during embryogenesis in humans. Several studies have shown that SOX11 is aberrantly expressed in various types of haematopoetic and solid malignancies, and appears to affect clinicopathological characteristics. For example, in mantle cell lymphoma, SOX11 serves as a diagnostic antigen and has been shown to be associated with superior outcome (Nordström et al. British Journal of Haematology 2014), although its role as a prognostic indicator remains controversial. In chronic lymphocytic leukemia, SOX11 was associated with inferior overall survival (Roisman et al. Tumor Biol 2015), whereas SOX11 expression correlated with superior outcome in epithelial ovarian cancer (Sernbo et al. BMC Cancer 2011). Various possible target genes and transcriptional programs have been identified, by which SOX11 may exert both repressive, and exaggerative, functions on proliferation, and potentially function as therapeutic targets in the future (Kuo et al. Oncogene 2015, Vegliante et al. Blood 2013). In Burkitt lymphoma (BL), two small series have reported expression of SOX11 in 30-50 % of cases (Mozos et al. Haematologica 2009, Dictor et al. Haematologica 2009). As of yet, no study has been performed specifically to evaluate the implication of SOX11 expression in BL. The aim of this study was to investigate the frequency of SOX11 positive BL cases in a joint cohort from Denmark and Sweden, and correlate its expression to clinical and pathological parameters. Methods: 45 BL cases were collected from Sweden and Denmark. Samples were analysed for expression of SOX11 and other immunohistochemical markers. Cases were classified classic BL or B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCLU) after pathology review. Clinical data were obtained from the Danish Lymphoma Database (LYFO) and the Swedish Lymphoma Registry. Additionally, 9 pediatric BL cases were analyzed for SOX11 expression, but with no clinical data available. Results: In the adult BL study population 14/45 (31 %) expressed nuclear staining of SOX11. The SOX11 positive subgroup had a higher median age (53 compared to 41), as well as a larger proportion with elevated LDH. Other prognostic factors were equally distributed between the groups. Although a similar proportion of patients received high-intensive chemotherapy in both subgroups, 3 (21 %) received no treatment in the SOX11 positive cohort. In this BL material, 28 (62 %) were classified classic BL and 17 (38 %) BCLU. There was a significant difference in SOX11 expression between classic BL and BCLU (p=0.03). Among classic BL SOX11 was seen in 12/28 (43 %) whereas in BCLU only 2/17 (12 %) expressed SOX11. Five-year overall survival (OS) in the SOX11 positive group was 57 %, compared to 77 % in the SOX11 negative cohort. When adjusting for treatment, BCLU and prognostic factors in multivariable analysis, no significant difference in outcome was seen between groups (hazard ratio: 2.5 95 % confidence interval: 0.4-13.9, p=0.3). When restricting analysis to classic BL cases only, there was no remaining difference in median age, and no significant difference in OS between SOX11 positive and negative patients in neither univariable nor multivariable analysis. In the pediatric cohort, 5/9 (56 %) expressed SOX11. Conclusion: SOX11 expression was found in less than half of classic BL, and in a small minority of BCLU. In contrast to SOX11 expression in other malignancies, SOX11 expression had no significant impact on outcome, in our cohort, when adjusting for prognostic factors, treatment and BCLU. Disclosures Brown: Bayer: Consultancy; Roche: Consultancy, Speakers Bureau.

Background: Peripheral T-Cell lymphomas (PTCLs) constitute approximately 10% of lymphoid malignancies and consist of several distinct entities based on pathologic and clinical characteristics. With the exception of a few subtypes (e.g., ALK-positive anaplastic large cell lymphoma (ALCL) and some primary cutaneous or leukemic forms of PTCL), a majority of PTCLs are aggressive as characterized by poor treatment response, rapid disease progression and poor overall survival. We have shown that landmark timepoints of event-free survival after diagnosis can stratify subsequent overall survival (OS) in diffuse large B-cell and follicular lymphoma. Here we evaluate this approach in newly diagnosed aggressive PTCLs treated with anthracyline-based or related chemotherapy. Methods. Newly diagnosed PTCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012. Clinical data were abstracted from medical records using a standard protocol. For this analysis, we included patients receiving anthracycline-based or other multiagent chemotherapy for the following PTCL subtypes: ALK-negative ALCL (N=24); angioimmunoblastic T-cell lymphoma (AITL, N=34); PTCL, not otherwise specified (NOS; N=60); enteropathy-associated T-cell lymphoma (EATL, N=8); extranodal NK/T-cell lymphoma, nasal type (ENKTL, N=11); and hepatosplenic T-cell lymphoma (HSTCL, N=1). Patients were prospectively followed, and event-free survival (EFS) was defined as time from diagnosis to progression, re-treatment, or death due to any cause. Landmark EFS timepoints were assessed at 12 (EFS12) and 24 (EFS24) months after the date of diagnosis. Subsequent OS was defined as time from a specific endpoint (diagnosis, event or EFS landmark). Replication was performed in a population-based cohort of T-cell lymphomas diagnosed from 2000-2009 from the Swedish Lymphoma Registry. Results. 138 eligible patients were enrolled in the MER from 2002-2012, the median age at diagnosis was 58 years (range, 19-88), 66% were male, 73% had Stage III-IV disease, and 33% had IPI 0-1. At a median follow-up of 47 months (range 11-120), 87 patients (63%) had an event and 70 patients (51%) had died. From diagnosis, only 60 patients were event-free at 12 months (EFS12 45%). Patients who failed to achieve EFS12 had a poor subsequent OS from event (median OS = 6.8 months, 95% CI: 5.3-14.0, figure 1). In contrast, patients who achieved EFS12 had a favorable subsequent OS (median unreached, figure 2). Of the 427 eligible patients in the Swedish registry, the median age at diagnosis was 66 years (range, 18-88), 63% were male, 68% had Stage III-IV disease, and 25% had IPI 0-1. PTCL subtypes were: ALK-negative ALCL (N=89); AITL (N=80); PTCL, NOS (N=183); EATL (N=44); ENKTL (N=24); and HSTCL (N=7). At a median follow-up of 86 months (range 40-158), 333 patients (79%) had an event and 316 patients (74%) had died. From diagnosis, 183 patients were event-free at 12 months (EFS12 44%). Similar to the MER cohort, Swedish patients failing EFS12 had poor subsequent survival (median OS = 3.7 months, 95% CI: 2.9-5.3, figure 1). Swedish patients achieving EFS12 had a favorable subsequent OS (median OS = 89 months, figure 2). Similar results were obtained when conducting landmark analysis at 24 months after diagnosis (EFS24). Conclusion. Relapse and re-treatment events within the first 12 months of diagnosis are associated with very poor OS in PTCL treated with anthracyclines or related chemotherapy, while patients achieving EFS12 have encouraging subsequent OS. Stratifying patients into prognostically distinct subsets using EFS12 may help focus biologic and biomarker studies. EFS12 has potential as an early endpoint for studies of newly diagnosed PTCL. Further investigation of determinants related to post-EFS12 survival is needed. Disclosures Maurer: Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Relander:Respiratorius: Patents & Royalties: valproate for DLBCL.

Burkitt lymphoma (BL) is a rare neoplasm constituting 1-2% of adult lymphomas. Our aims in this study were to establish prognostic factors for overall survival in adult BL and evaluate the efficacy of different chemotherapy regimens in a population based setting. The study population was collected from the Swedish Lymphoma Registry 2000-2010. During this period, 156 adult patients with BL were identified. In multivariate analysis, age and performance status (PS) were significant adverse prognostic factors for overall survival. A modified prognostic index, based on: age >40 years, PS >1, and lactate dehydrogenase > upper limit of normal (ULN) was proposed. Patients with a score of 0-1, 2, and 3 were found to have a 2-year survival of 91.2%, 58.4%, and 27.5%, respectively. High-intensity regimens were associated with more favorable overall survival. Rituximab addition was not significantly associated with improvement in survival. A modified prognostic index may be valuable for adult BL, as proposed.

In recent years, more intensive chemotherapy regimens for mantle cell lymphoma (MCL) have been associated with prolongation of survival. In this study, our aim was to investigate prognostic factors and evaluate improvement in survival in MCL on a population level. The cohort included all patients diagnosed with MCL from 1 January 2000 to 31 March 2010 in the Swedish Lymphoma Registry. At total of 785 patients with MCL were identified. Age, performance status, and B-symptoms were significant prognostic factors for overall survival (OS) in multivariate analysis. In addition, OS was markedly improved (hazard ratio 0.8, 95% confidence interval 0.7-0.9) for patients diagnosed during the latest time period, 2006-2010, also when corrected for prognostic factors as above. Estimated OS at 3 years was 62%, compared to 47% for patients diagnosed earlier (p < 0.01). The reasons for this dramatic improvement in OS are not yet clear, but may be due to the introduction of specific and more potent therapeutic regimens.

Prenylation is a post-translational hydrophobic modification of proteins, important for their membrane localization and biological function. The use of inhibitors of prenylation has proven to be a useful tool in the activation of apoptotic pathways in tumor cell lines. Rab geranylgeranyl transferase (Rab GGT) is responsible for the prenylation of the Rab family. Overexpression of Rab GGTbeta has been identified in CHOP refractory diffuse large B cell lymphoma (DLBCL). Using a cell line-based model for CHOP resistant DLBCL, we show that treatment with simvastatin, which inhibits protein farnesylation and geranylgeranylation, sensitizes DLBCL cells to cytotoxic treatment. Treatment with the farnesyl transferase inhibitor FTI-277 or the geranylgeranyl transferase I inhibitor GGTI-298 indicates that the reduction in cell viability was restricted to inhibition of geranylgeranylation. In addition, treatment with BMS1, a combined inhibitor of farnesyl transferase and Rab GGT, resulted in a high cytostatic effect in WSU-NHL cells, demonstrated by reduced cell viability and decreased proliferation. Co-treatment of BMS1 or GGTI-298 with CHOP showed synergistic effects with regard to markers of apoptosis. We propose that inhibition of protein geranylgeranylation together with conventional cytostatic therapy is a potential novel strategy for treating patients with CHOP refractory DLBCL.

Male gender is an adverse prognostic factor in Hodgkin's lymphoma, but no such association has yet been established in non-Hodgkin lymphomas. Here, we have evaluated whether gender has prognostic impact on the survival of patients with B-cell non-Hodgkin lymphoma in the postrituximab era of lymphoma therapies. The study populations consisted of 217 diffuse large B-cell lymphoma (DLBCL) and 110 follicular lymphoma (FL) patients treated with immunochemotherapy. Hundred and sixty chemotherapy-treated DLBCL patients served as a control group. According to Kaplan-Meier analyses, female patients had a significantly better progression-free survival than men both in DLBCL (4 yr PFS 75% vs. 60%; P= 0.013) and in FL (4 yr PFS 68% vs. 52%, P=0.036) patients treated with immunochemotherapy. In chemotherapy-treated DLBCL patients, no difference in survival between the genders was found. The results support the idea that women seem to respond better to rituximab.

The efficacy and safety of zanolimumab (HuMax-CD4) in patients with relapsed or refractory peripheral T Cell lymphoma (PTCL) was evaluated. Twenty-one adult patients with relapsed or refractory CD4(+) PTCL of non-cutaneous type (angioimmunoblastic T cell lymphoma (AITL) n = 9, PTCL-not otherwise specified (NOS) n = 7, anaplastic large cell lymphoma (ALCL) n = 4 and enteropathy type T cell lymphoma n = 1) were treated in a single-arm multi-centre study, with weekly intravenous infusions of zanolimumab 980 mg for 12 weeks. Median age was 69 years (range 26-85). Seventeen of the patients had advanced stage disease (Ann Arbor stages III-IV). Objective tumour responses were obtained in 24% of the patients with two complete responses unconfirmed (CRu) and three partial responses (PR). One of the CRus lasted more than 252 d. Responses were obtained in different PTCL entities: AITL (n = 3), ALCL (n = 1) and PTCL-NOS (n = 1). In general, the trial drug was well tolerated with no major toxicity. Zanolimumab at a dose of 980 mg weekly demonstrated clinical activity and an acceptable safety profile in this poor-prognosis patient population, suggesting that the potential benefit combining zanolimumab with standard chemotherapy in the treatment of PTCL should be investigated.

Background The transcription factor SOX11 plays an important role in embryonic development of the central nervous system (CNS) and is expressed in the adult immature neuron but is normally not expressed in any other adult tissue. It has recently been reported to be implicated in various malignant neoplasms, including several lymphoproliferative diseases, by its specific expression and in some cases correlation to prognosis. SOX11 has been shown to prevent gliomagenesis in vivo but the causes and consequences of aberrant expression of SOX11 outside the CNS remain unexplained. Results We now show the first function of SOX11 in lymphoproliferative diseases, by demonstrating in vitro its direct involvement in growth regulation, as assessed by siRNA-mediated silencing and ectopic overexpression in hematopoietic malignancies. Gene Chip analysis identified cell cycle regulatory pathways, including Rb-E2F, to be associated with SOX11-induced growth reduction. Furthermore, promoter analysis revealed that SOX11 is silenced through DNA methylation in B cell lymphomas, suggesting that its regulation is epigenetically controlled. Conclusions The data show that SOX11 is not a bystander but an active and central regulator of cellular growth, as both siRNA-mediated knock-down and ectopic overexpression of SOX11 resulted in altered proliferation. Thus, these data demonstrate a tumor suppressor function for SOX11 in hematopoietic malignancies and revealed a potential epigenetic regulation of this developmentally involved gene.

We have previously shown that expression of CD40 has a favorable prognostic impact in diffuse large B-cell lymphoma (DLBCL) after anthracycline-based chemotherapy. Here we examined the prognostic value of immunohistochemically defined CD40 expression in 95 patients with DLBCL treated with both anthracycline-based chemotherapy and rituximab. Using a 10% cut-off level, 77% of the patients had CD40-positive tumors and showed a superior overall survival (p = 0.02 log-rank, hazard ratio 0.35, 95% CI 0.14-0.88, p = 0.03 Cox regression). When adjusted for International Prognostic Index in multivariate analysis, CD40 was not an independent prognostic factor (hazard ratio 0.39, 95% CI 0.15-1.04, p = 0.06 Cox regression). However, even after the introduction of immunochemotherapy, CD40 has a potential prognostic impact in DLBCL. Additional and larger studies are necessary, regarding the immunohistochemical robustness of CD40 and the biological mechanisms that contribute to the superior prognosis in CD40-expressing DLBCL.

Gene expression profiling studies initially enabled diffuse large B-cell lymphoma to be divided into germinal center and activated B-cell-like subtypes, which define high- and low-risk patient groups when treated with chemotherapy. Attempts to reproduce the prognostic classification immunohistochemically have, however, provided inconsistent results. The aim of this study was to determine whether modified immunohistochemical classification of cell of origin focusing on activated B-cell-like markers could be used to predict the outcome of immunochemotherapy-treated diffuse large B-cell lymphoma patients. The expression of CD10, Bcl-6, MUM1/IRF4, Bcl-2, and FOXP1 was determined immunohistochemically from 88 samples of diffuse large B-cell lymphoma patients treated uniformly with R-CHOP. When the modified classification using MUM1/IRF4 and FOXP1 positivities as activated B-cell-like markers was applied to distinguish the patients between the activated B-cell-like and other diffuse large B-cell lymphoma subtypes, a significantly worse outcome was seen for the patients with the activated B-cell-like phenotype (3-year failure-free survival 63 vs 82%, P=0.048, overall survival 69 vs 85%, P=0.110). Similarly, according to the Muris algorithm, the group 2 patients representing Bcl-2-positive post-germinal center patients showed an inferior outcome in comparison to the group 1 patients (failure-free survival 59 vs 81%, P=0.041, overall survival 67 vs 82%, P=0.159). In contrast, when the classification of the same cohort was performed according to the Hans algorithm, no significant difference in survival was observed between the germinal center and non-germinal center patients. In conclusion, the data suggest that both the modified activated B-cell-like and Muris classifications define the non-germinal center phenotype as an adverse risk factor in R-CHOP-treated diffuse large B-cell lymphoma patients.

Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) show varying responses to conventional therapy, and this might be contributed to the differentiation stage of the tumor B-cells. The aim of the current study was to evaluate a panel of kinases (ZAP70, PKC-beta I and II and phosphorylated PKB/Akt) and phosphatases (PTEN, SHP1 and SHP2) known to be frequently deregulated in lymphoid malignancies. De novo DLBCL cases were divided into two subgroups, the germinal center (GC) group (14/28) and the non-germinal center (non-GC) or activated B-cell (ABC) group (14/28). ZAP70 and PKC-beta II were expressed in a significantly higher percentage of tumor cells in the clinically more aggressive non-GC group compared with the prognostically favourable GC group. Also, the subcellular localization of PKC-beta I and II differed in DLBCL cells, with the PKC-beta I isoform being expressed in both the cytoplasm and nucleus, while PKC-beta II was found exclusively in the cytoplasm. Loss of nuclear PTEN correlated with poor survival in cases from both subgroups. In addition, five cell lines of DLBCL origin were analyzed for protein expression and for mRNA levels of PTEN and SHP1. For the first time, we show that ZAP70 is expressed in a higher percentage of tumor cells in the aggressive non-GC subgroup of DLBCL and that PKC-beta I and II are differently distributed in the two prognostic subgroups of de novo DLBCL.

To study the differential expression of cell membrane-bound receptors and their potential role in growth and/or survival of the tumor cells, highly purified follicular lymphoma cells were analyzed, using gene expression analysis, and compared to non-malignant B cell populations. Filtering the genome for overexpressed genes coding for cell membrane-bound proteins/receptors resulted in a hit list of 27 identified genes. Among these, we have focused on the aberrant over expression of CX3CR1, in different types of B cell lymphoma, as compared to non-malignant B cells. We show that CX3CR1, which normally is not expressed on B cells, is expressed both at the mRNA and protein level in several subtypes of lymphoma. CX3CR1 has also shown to be involved in the homing to specific tissues that express the ligand, CX3CL1, in breast and prostate cancer and may thus be involved in dissemination of lymphoma.

Objective: In this study, our aim was to investigate how different immunohistochemical techniques may influence the result of BCL6 positivity and categorization in germinal center (GC) and non-GC derived diffuse large B-cell lymphoma (DLBCL), as it has been proposed that classification of DLBCL according to cell-of-origin by immunohistochemistry may be performed as a routine procedure in the diagnostic workup. However, a number of technical issues need to be solved before introducing this as a standard technique. Methods: Tumor specimens from 122 patients with de novo stage II-IV disease, adequately treated with anthracycline-containing chemotherapy regimens were collected. Immunohistochemical expression of BCL6, CD10, and MUM-1/IRF4 was examined using a tissue microarray (TMA) technique. BCL6 and CD10 were also evaluated on whole tissue sections. Results: Due to profound tissue heterogeneity, BCL6 showed a wide range of positivity, with a high number of false negative results by TMA (25% positive), compared to 53% on whole tissue sections (WTS). CD10 was more homogeneously expressed, and TMA results corresponded better to WTS. Consequently, the results from categorization into GC and non-GC DLBCL differed considerably by use of the two methods, and resulted in very different outcome in terms of overall survival. Conclusion: Immunohistochemical GC-status determined on TMA is not reliable enough to be used for individual treatment decisions in DLBCL, mostly due to difficulties in interpreting BCL6 status.

During recent years the neural transcription factor SOX11 has been established as an important biomarker for mantle cell lymphoma. SOX11 is both a diagnostic and prognostic antigen, and may potentially be used for treatment selection for younger patients, in relation to protocols including high dose chemotherapy. The molecular pathways involved are still not fully elucidated and, as SOX11 can interact with several co-transcription factors, functional assays need to be carefully designed to pinpoint SOX11-specific function in a defined cellular context. Furthermore, as SOX11 belongs to a large family of homologous proteins, analysis of SOX11 has been limited by the availability of specific antibodies for detection and pull-down. In this review, we discuss the emerging role of SOX11 in mantle cell lymphoma and discuss the potential impact in relation to tumorigenesis, diagnostics, prognostics, and therapy. (Less)

Background Despite recent advances in molecular profiling of diffuse large B-cell lymphoma (DLBCL), only a few biomarkers currently have an impact on treatment. In a previous study we could observe the heterogeneity of DLBCL in the plasma immunoprofile from DLBCL patients, by use of recombinant antibody microarrays. By unsupervised hierarchical clustering, an immunoprofile of 23 plasma proteins could divide patients into two subgroups with significantly different overall survival (OS). In this study we aimed to expand the immunoprofiling with longitudinal plasma samples from high risk DLBCL patients, to search for novel prognostic and potentially predictive markers. Material and Methods Plasma samples from 126 high risk DLBCL patients included in a phase II clinical trial of the Nordic Lymphoma Group (CRY04) were collected at diagnosis, during and after treatment, and in the event of progression or relapse. Inclusion criteria were age 18-65 years, primary diffuse large B-cell lymphoma without CNS involvement, age-adjusted International Prognostic Index (aaIPI) 2-3 and WHO performance score 0-3. Six courses of R-CHOEP-14 were given followed by systemic CNS prophylaxis with one course of high-dose cytarabine and one course of high-dose methotrexate. Additionally, age and sex matched controls (n = 40) were included. Two hundred and eighty-three recombinant scFv antibody fragments directed against 97 known serum antigens, mainly immunoregulatory proteins, were selected from phage display libraries to be used in the antibody microarrays. Results Immunoprofiles distinguishing DLBCL patients from healthy controls were identified. Furthermore, a different protein expression was found in patients with aaIPI 3 versus 2 as well as in patients with shorter versus longer progression free survival (PFS). The kinases CDK-2 and BTK were upregulated both in patients with higher aaIPI score and in patients with shorter PFS. Comparing the patients who developed disease progression with those who did not, seven differentially deregulated proteins were identified including the phosphatase PTP-1B, the chemokine MCP-1, and the cytokines IL-4, IL-6 and IL-12, all previously implicated in B-cell lymphoma pathogenesis. In addition, results showed that subdivision of patients according to immunoprofile as defined in our previous study, could be performed also in the present patient cohort. The immunoprofile comprises T-helper (TH)1 cytokines, TH2 cytokines, complement proteins, chemokines, enzymes, and membrane proteins. The 23 included proteins are β-galactosidase, C1 esterase inhibitor, C4, C5, Cystatin C, Eotaxin, GLP-1 R, GM-CSF, HLA-DR/DP, IgM, IL-1ra, IL- 2, IL- 3, IL- 6, IL- 10, IL- 12, Leptin, MCP-1, MCP-3, Mucin-1, PSA, TNF-α, and TNF-β. Although not significant, a potential association to PFS and OS could be observed between the two generated subgroups. Finally, expression of IL-10 was shown to improve the prognostic value of aaIPI regarding both PFS and OS. Conclusion Protein expression profiling of plasma from high risk DLBCL patients provided novel insights into the biology of DLBCL. New candidate prognostic markers were identified which could potentially guide us in the prediction of outcome and in the choice of treatment for DLBCL patients. However, as this study was aimed for discovery, the findings must be validated in future studies with independent patient cohorts. Disclosures No relevant conflicts of interest to declare.

Introduction Disease relapse involving the central nervous system (CNS) carries a dismal prognosis in patients with aggressive lymphoma. Risk factors for CNS-relapse have included involvement of lymphoma at specific anatomical sites, proliferation rate and high tumor burden. The risk and importance of CNS-relapse in peripheral T-cell lymphomas (PTCL) has been very little studied. So far, the only study focusing on CNS-relapse in PTCL found elevated LDH and paranasal sinus involvement to be independent risk factors and that CNS-relapse was associated with an inferior survival. Recently, several studies have highlighted the dismal prognosis of relapsed PTCL in general. In this study we aimed at analyzing risk factors for CNS involvement in first relapse and the outcome of these patients, in a large population-based cohort of PTCL patients. Materials and methods Through the Swedish Lymphoma Registry we identified all adult (>18 years) patients diagnosed with PTCL between January 1st 2000 and December 31st 2009. Primary cutaneous, primary leukemic types and T-cell lymphoblastic lymphoma were excluded. Information on first relapse was collected from patient files retrospectively after informed consent. Results Out of 755 patients identified through the registry, 10 patients had CNS involvement at diagnosis and were excluded from further analyses. Data on first relapse was available for 618, and among these 369 patients experienced relapse or progression. Thirty-one patients (5.0 %) experienced progression or relapse involving the CNS after a median time of 4.3 months (range 1.1-45 months) from diagnosis. Thirteen patients experienced an isolated CNS relapse/progression and 18 as part of a systemic relapse. Sixteen patients relapsed after responding to primary therapy (10 CR, 6 PR), and 15 patients with refractory disease had CNS-progression (1 SD, 14 PD). Histologic subtypes among the 31 patients were ALK-positive anaplastic large cell lymphoma (ALCL) (n=3), ALK-negative ALCL (n=3), ALK-unknown ALCL (n=1), angioimmunoblastic T-cell lymphoma (n=3), peripheral T-cell lymphoma NOS (n=13), enteropathy-associated T-cell lymphoma (n=3), NK/T-cell lymphoma nasal type (n=1), hepatosplenic T-cell lymphoma (n=1) and unclassified T-cell lymphoma (n=1). All 31 patients had received chemotherapy with curative intent and 6 received intrathecal prophylaxis. In multivariable analysis, the presence of B-symptoms (HR 2.79 95% CI 1.14-6.82, p=0.024), >1 extranodal site of disease (HR 3.28[1.41-7.64], p=0.006) and skin involvement (HR 3.06 [1.10-8.49], p=0.032) were independent risk factors for CNS relapse. Median survival for patients with CNS involvement at relapse or progression was 3.3 months (range 0-124) compared to 3.7 (range 0-129) for patients without CNS involvement and CNS involvement was not a risk factor for OS after relapse/progression (HR 1.08 [0.73-1.59], p=0.700). For relapsing patients only age was predictive of inferior survival (1.014 [1.002-1.027], p=0.026) whereas in patients with primary refractory disease, male gender predicted inferior survival (2.93 [1.54-5.58], p=0.001) and angioimmunoblastic T-cell lymphoma was associated with better survival (0.41 [0.18-0.95], p=0.037). Conclusions CNS involvement, isolated or as part of a systemic first relapse, occurred in 5% of the patients in our series, which is similar to the incidence in larger series dominated by B-cell lymphomas. In our cohort, B-symptoms, >1 extranodal site of disease and skin involvement were independent predictors for CNS-relapse. The outcome of relapsed patients was very poor in general, and CNS-involvement did not convey worse outcome compared to patients with systemic relapse only. With current treatment strategies the uncommon CNS-relapses seem to be a problem of lower magnitude compared to the frequent systemic relapses. Future improvements in the treatment of PTCLs could possibly increase the importance of identifying patients at risk for CNS-relapse, and our study provides data on this poorly described complication. Disclosures No relevant conflicts of interest to declare.

Background: The current standard treatment for patients with diffuse large B-cell lymphoma (DLBCL) is Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (R-CHOP). Two large randomised trials have been unable to establish a significant difference in outcome between patients receiving R-CHOP at 21 versus 14 day intervals regardless of age (Cunningham et al Lancet 2013, Delarue et al Lancet 2013). Another means of intensifying R-CHOP is by the addition of etoposide (R-CHOEP-14). As of yet, no randomised study in the rituximab era has been performed specifically evaluating the addition of etoposide. The aim of this study was to compare the chemotherapy regimens used to treat DLBCL in Sweden (R-CHOP-21, R-CHOP-14, R-CHOEP-14) among patients aged ≤70 in terms of overall survival, adjusted for clinical prognostic factors. Methods: The study population was identified through the Swedish Lymphoma Registry (SLR) 2007-2012. Data was analysed using STATA and SPSS. Age was modelled as splines in the multivariable analysis. Results: A total of 1745 patients aged ≤70 were identified in the SLR during the time-frame of this study. Median age was 61 years (range 18-70). Of these, 1331 had received R-CHOP-21 (n=302), R-CHOP-14 (n=872) or R-CHOEP-14 (n=157) and were included in the study. Median follow-up time for surviving patients was 49 months. Three-year overall survival rates were 86.7%, 79.6% and 87.5% for the patients who received R-CHOP-21, R-CHOP-14 and R-CHOEP-14 respectively. There was a significant disparity in the distribution of prognostic factors among patients receiving the various chemotherapy regimens with a lower proportion of patients with elevated serum lactate dehydrogenase (S-LDH), performance status >1, stage III-IV and presence of bulky disease (>10 cm) in the R-CHOP-21 group compared to the other regimens. As expected, the most intensive regimen, R-CHOEP-14 was more frequently given to younger patients (median age 49) with high-risk prognostic features. When adjusting for significant prognostic factors (age, performance status, S-LDH, bulky disease, stage and gender) in a multivariable Cox regression model, R-CHOEP-14 was found to be significantly superior both to R-CHOP-21 (Hazard Ratio (HR): 0.53, Confidence Interval (CI):0.3-0.9, p=0.026) and R-CHOP-14 (HR:0.63, CI:0.4-1.0, p=0.048). No significant difference between R-CHOP-14 and R-CHOP-21 was found (HR: 0.84, CI: 0.6-1.2, p=0.3), consistent with findings from randomised trials performed. Conclusion: In this population based series of DLBCL, the more intensive regimen R-CHOEP-14 was associated with superior overall survival in patients aged up to 70 years, indicating that this may be considered among the standard treatment options for this patient population. R-CHOEP-14 should preferably be compared to R-CHOP-21 in a randomised setting in order to further elucidate which patient groups that benefit the most from treatment intensification. Disclosures No relevant conflicts of interest to declare.

Background Poorly differentiated midline carcinoma with a translocation between chromosomes 15 and 19, i.e. t(15;19), has been recognized as a distinct clinical entity for over a decade. This tumor affects young individuals, shows a rapidly fatal clinical course despite intensive therapy. The t(15;19) results in the fusion oncogene BRD4-NUT. Information concerning treatment of this rare disorder is scarce. Case presentation A 30-year-old woman was admitted with a rapidly progressing tumor in the mediastinum, cervical lymph nodes, vertebral column and the epidural space. Pathological, cytogenetic, FISH and PCR analysis revealed a glycogenated carcinoma rarely expressing cytokeratins and showing t(15;19) and BRD4-NUT gene rearrangement. The patient was initially treated with a Ewing sarcoma chemotherapy regimen, but had rapid progression after two cycles. She then received docetaxel and radiotherapy, which resulted in almost complete disappearance of the tumor. Conclusion Docetaxel may be considered for initial chemotherapy in young patients presenting with a midline carcinoma with bone marrow involvement and cytogenetic and molecular genetic finding of a t(15;19)/BRD4-NUT-rearrangement. We herein describe, in detail, the laboratory methods by which the BRD4-NUT -rearrangement can be detected.

Diffuse large B-cell lymphoma (DLBCL) has been shown to be comprised of at least two prognostic entities, depending on its resemblance to normal germinal center or activated B cells, using global gene expression profiling. Also, the expression patterns of bcl-6, CD10 and IRF-4 (also known as MUM1) have been suggested as alternative means of identifying the germinal- and nongerminal center (activated B-cell like) groups. In the present study, we evaluated by immunohistochemistry the expression patterns of CD10, bcl-6, IRF-4 and bcl-2 in a large material of 161 DLBCL patients. Using two different approaches, patients with germinal center phenotype displayed a significantly better survival than the nongerminal center group. Positive staining for bcl-6 or CD10 predicted for superior survival, while expression of IRF-4 alone showed no association with prognosis. Furthermore, expression of bcl-2 was associated with worse event-free survival and overall survival. In a multivariate analysis, a high international prognostic index score (3-5), non-GC phenotype and bcl-2 were independent adverse prognostic factors. Here we confirm the prognostic importance of determining the germinal- or nongerminal center phenotype in patients with DLBCL.

Substantial research has been dedicated to the study of the relationship between genetic mechanisms regulating cell functions in tumors and how those tumors respond to various treatment regimens. Because these mechanisms are still not well understood, we have chosen to study the genetic makeup of 57 tumor samples from patients with follicular lymphoma (FL). Our goal was to develop a prognostic tool, which can be used as an aid in determining FL patients with tumors genetically predisposed to a successful treatment with the CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone) regimen. To select relevant genes, high-density oligonucleotide arrays were used. There were 14 genes highly expressed in FL patients that responded well to CHOP chemotherapy, and 11 of these were involved in G2/M transition of the cell cycle, in mitosis, or in DNA modulation. A high expression of CCNB1 (cyclin B1), CDC2, CDKN3A, CKS1B, ANP32E, and KIAA0101, but not of the proliferation-related antigen Ki-67, was associated with better survival rate in a univariate analysis. CCNB1 expression had an independent prognostic value when included in a multivariate analysis together with the 5 parameters of the follicular lymphoma international prognostic index.

Mantle cell lymphoma (MCL) is believed to originate from a naive B cell. However, we recently demonstrated that a subset of MCL displayed mutated V-H genes. We also reported restricted use of certain V-H genes. To assess the prognostic impact of these new findings, we performed V-H gene analysis of 110 patients, revealing that 18 (16%) patients had mutated and 92 (84%) patients had unmutated V-H genes. Because the mutation rate was low in the mutated group (2.2%-6.7%), further investigation of the germline V-H gene in T cells from 5 patients with mutated V-H genes was carried out; results showed that the unrearranged V-H gene was identical to the published sequence. These data confirm that the base pair substitutions within the rearranged V-H genes represent hyper-mutations, and indicate germinal center exposure. However, V-H gene mutation status did not correlate with prognosis because there was no difference in clinical outcome between the unmutated and mutated groups. The most frequently used V-H genes were V(H)3-21 (21 patients) and V(H)4-34 (19 patients). A novel finding was that V(H)3-21(+) MCL almost exclusively ex-pressed X light chains and displayed highly restricted use of the V(lambda)3-19 gene. V(H)3-21(+) patients had longer median survival than the remaining patients (53 vs 34 months; P = .03), but they tended to be younger at diagnosis. The combined use Of V(H)3-21/V(lambda)3-19 suggests a possible role for antigen(s) in the pathogenesis of these tumors and indicates that V(H)3-21(+) patients constitute a new MCL entity. (C) 2003 by The American Society of Hematology.

In search for subgroups of diffuse large B-cell lymphoma (DLBCL) with different histogenetic origin and prognosis, as has been described by gene expression profiling, we examined tumor specimens from 125 patients with DLBCL, uniformly treated by either cyclophosphamideAdriamycin-vincristine-prednisone or methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin in a multicenter trial set by the Nordic Lymphoma Group 1989-1994.Bcl-6, CD10, and CD40 were chosen as markers for a germinal center phenotype, CD23 as a marker of pre/early germinal center origin, and CD138 as a marker for postgerminal center origin. In addition, expression of the apoptotic regulators bcl-2 and bax was analyzed. Immunohistochemical analysis was performed using the EnVision method.CD10 was positive in 51%, bcl-6 in 97%, and CD138 only in 2% of the cases. No prognostic conclusions could be drawn from analysis of these factors. CD40 was positive in 76% of the cases. This group was associated with superior time to treatment failure (P = 0.027) and overall survival (OS; P = 0.0068). By Cox regression analysis, positivity for CD40 was shown to be a prognostic factor for OS, independent of International Prognostic Index. CD23 was positive in 16% of the cases (all CD5 negative and all CD40 positive). This group showed a strong tendency for better OS (P = 0.033). CD40 expression correlated with bax but not with bcl-2 expression.CD23 and CD40 expression seems to be prognostically favorable in DLBCL. This may be secondary to a germinal center origin or attributable to increased apoptosis via induction of bax and/or enhanced T-cell interaction, resulting in improved autologous tumor response. Confirmatory studies are necessary.

Residual masses are frequently found in patients with aggressive lymphomas, following therapy. A study was undertaken to determine whether initial tumour size, changes during treatment, or size of the residual mass could provide prognostic information. Computed tomography (CT) examinations were carried out before, midway and after completion of chemotherapy in 37 patients with aggressive lymphoma with residual mass after treatment. The tumours were measured for both the greatest diameter sizes and area. The size of the residual mass correlated with the tumour size at diagnosis. Neither a large tumour size before treatment nor a large residual mass after treatment correlated with an increase in rate of relapse. The initial tumour reduction (measured after completion of half of the planned chemotherapy) was less pronounced in relapsing patients compared to relapse-free patients. Using a cut-off level of 70% tumour reduction (measured after completion of half of the planned chemotherapy), 66% of patients with a tumour reduction of < 70% relapsed, compared with 22% (p < 0.05) in those with more marked tumour regression.

Introduction High-dose cytarabine containing immuno-chemotherapy followed by autologous stem cell transplantation (ASCT) has been established as standard first-line treatment in younger mantle cell lymphoma (MCL) patients (ESMO guideline, Ann Oncol 2013). However, the role of total body irradiation (TBI) as conditioning regimen for ASCT has not been clarified so far. A retrospective EBMT survey of 418 MCL patients suggested a benefit of TBI with respect to the rate of relapse in patients who achieved a partial remission before ASCT (Rubio et al., ASH 2010). We combined the individual patient data of the Nordic MCL2 trial (Geisler et al., Blood 2008), the HOVON 45 trial (van’t Veer et al., BJH 2008, both without TBI), and the high-dose cytarabine containing study arm of the European MCL Younger trial (Hermine et al., ASH 2012, with TBI) to evaluate potential differences in long term outcome. Methods All trials included patients with advanced stage MCL up to 66 years and a central review of histology. Induction treatment of Nordic MCL2 consisted of 6 alternating courses of Maxi-CHOP or high-dose cytarabine (12g/m2 per cycle, 8g/m2 in patients > 60 years, total cumulative dose 24-36g/m2) combined with 4-6 cycles rituximab, in HOVON 45 three courses R-CHOP were followed by one cycle of high-dose cytarabine (16g/m2), and in MCL Younger patients received 6 alternating courses of R-CHOP or R-DHAP (4g/m2 cytarabine per cycle, total cumulative dose 12g/m2). Conditioning before ASCT consisted of BEAM or BEAC in Nordic MCL2, and BEAM in HOVON 45, whereas a TBI-containing regimen (TAM: 10 Gray TBI, 6g/m2 cytarabine, 140mg/m2 melphalan) was applied in MCL Younger. We compared baseline characteristics, progression free survival (PFS) overall survival (OS) after ASCT from the three patient cohorts with adjustment for MIPI (Hoster et al., Blood 2008) and quality of remission before ASCT. Results In Nordic MCL2, HOVON 45, and MCL Younger 145, 61, and 171 patients were transplanted in complete (CR) or partial (PR) remission (median age 57, 55, and 56 years, p=0.24). According to MIPI, 46%, 56%, and 67% were low risk, whereas 22%, 13%, and 11% were high risk patients (p=0.006). Five-year PFS after ASCT was 61%, 50%, and 78%, respectively (p Conclusion The longer PFS after ASCT of MCL Younger compared to HOVON 45 patients may be due to the different time schedule of cytarabine during induction or to a higher efficacy of TBI vs. BEAM, as the total chemotherapy doses were comparable and we adjusted for MIPI. We could not see an improved PFS after ASCT of MCL Younger compared to Nordic MCL2 patients transplanted in CR or unconfirmed CR and, after adjustment for the different risk profiles, this was also not clearly seen for patients transplanted in PR. Taking into account the substantially higher cytarabine dose in Nordic MCL2 during induction one might speculate that this fact at least partially compensated for a higher efficacy of TBI. Multivariable analyses incorporating additional prognostic factors (Ki-67 and MRD) will help to clarify the impact of the individual parts of the current multimodal approach in younger MCL patients. On behalf of the European Mantle Cell Lymphoma Network Disclosures: No relevant conflicts of interest to declare.

Introduction Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, previously correlated to a short survival of 3-5 years. Modern clinical protocols, combining immunochemotherapy, high-dose therapy and autologous stem cell transplantation (ASCT) have remarkably improved survival reaching a median survival of more than 10 years. To enable patient stratification, a MCL international prognostic index (MIPI) has been created similar to the international prognostic index (IPI) and follicular lymphoma international prognostic index (FLIPI). However, MIPI alone, or in combination with Ki-67 (MIPI-B), has shown limited use in guiding treatment decisions by poorly separating low and intermediate risk group patients treated with novel clinical protocols. The transcription factor SOX11 has during recent years been shown to be an important diagnostic, prognostic and functional antigen in MCL. We have recently developed a monoclonal antibody to target SOX11 in clinical applications such as IHC and FACS. Using this antibody with improved specificity, we investigated the prognostic use of SOX11 in the homogenously treated Nordic MCL2 and MCL3 cohort. Additionally, we investigated the prognostic value by combining SOX11 and MIPI/MIPI-B. Methods The Nordic MCL2 (n=58) and MCL3 (n=69) patient cohort, treated with first line intensive immunochemotherapy, followed by high-dose chemotherapy and ASCT as well as addition of ibritumomab radioimmunotherapy for MCL3 patients, was stained for SOX11 expression in relation to clinicopathological and biological parameters such as Ki-67, P53 and Cyclin D1. Results In total, 95 % of the Nordic MCL2/3 cohort expressed SOX11, similar to previous studies. The nuclear SOX11 stainings were classified based on both intensity and frequency; negative, weak, strong ≤ 30 % and strong > 30 %. We show that high protein levels of SOX11 (strong > 30 %) correlate to an increased survival among MCL2/3 patients (p=0.02). A positive correlation between SOX11 and Cyclin D1 (p=0.006) was identified while both P53 (p Conclusions We show that the expression level of SOX11 correlates to improved OS in the Nordic MCL2/3 cohort, and this is the first time SOX11 has been correlated to survival in a homogenously treated cohort. Furthermore, the use of SOX11 can separate MIPI low/intermediate patients into two groups with significant difference in OS. SOX11 in combination with MIPI-B defines both a large group of patients with great outcome that benefit from the current treatment and a distinct reduced high risk group of patients with a short survival that potentially should receive alternative treatment. Thus, combining SOX11 status and the MIPI/MIPI-B can be used to stratify patients for treatment selection. Disclosures: No relevant conflicts of interest to declare.

Background Despite the advent of rituximab (R)-based chemoimmunotherapy, outcome for patients with high-risk diffuse large B-cell lymphoma (DLBCL) continues to be suboptimal, and the risk of central nervous system (CNS) progression is high. In a previous Nordic phase II study with dose-dense chemoimmunotherapy followed by systemic CNS prophylaxis, the CNS progression rate was lower than expected (4.5%), but all events occurred within 6 months after initiation of therapy (Holte et al., Ann Oncol 2013). Hence, in the present study, systemic CNS prophylaxis was moved to the beginning of therapy and CNS targeted therapy was further intensified by adding intrathecally administered liposomal AraC. Methods Inclusion criteria are age 18-65 years, primary DLBCL or grade 3B follicular lymphoma without clinical or radiological signs of CNS disease and cytology negative cerebrospinal fluid (CSF), age adjusted IPI 2-3, WHO performance score ≤3, and/or site specific risk factors for CNS recurrence. Treatment consists of two courses of high dose (HD)-Mtx in combination with R-CHOP14, four courses of R-CHOEP14 and a course of HD-AraC with R. In addition, liposomal AraC is administered intrathecally in courses 1, 3 and 5. All courses are administered with support of pegfilgastrim. Indications for radiotherapy are bulky masses at diagnosis and localized PET positive residual disease not eligible for biopsy. Primary endpoints are failure-free survival at 3 years, and CNS progression rate at 18 months. A secondary aim is to elucidate if CSF cytology negative/flow cytometry (FC) positive cases carry an increased risk of CNS progression with the present regimen. Results Of the accrued 84 patients by July 22, 2013, 70 had a complete set of baseline data. Median age was 55 years (range 20-64). The majority presented with DLBCL (96%), advanced-stage disease (94%), elevated LDH (94%), B-symptoms (67%), and 49% with >1 extranodal site. Seven CSF-samples were FC positive. Data on toxicity, response and relapse rates were registered for 45 patients. One toxic death due to pneumonia was reported. Grade 4 hematological toxicity and infections were observed in 78% and 11% of the patients, grade 3-4 mucositis and gastrointestinal toxicity in 27% and 42%, and grade 3 arachnoiditis in 2.2% of the patients. CR, CRu, PR and PD rates at the end of chemoimmunotherapy were 69.0%, 14.3%, 14.3% and 2.4 %, respectively. After a median follow up time of 19 months, four patients have relapsed, two of whom with fatal CNS manifestations. Conclusions Preliminary results indicate highly satisfactory response rates and reasonable toxicity despite intensive therapy. HD-Mtx in combination with R-CHOP in the beginning of therapy and further intensification of treatment with CNS targeted liposomal AraC seem feasible and safe. ClinicalTrials.gov Identifier: NCT01325194 Disclosures: Leppa: Amgen: Research Funding; Mundipharma: Honoraria, Research Funding. Holte:Mundipharma: Honoraria, Research Funding; Amgen: Research Funding.