Abstract: Follicular Lymphoma (FL) is the most common indolent lymphoma derived from light zone germinal center B cells and characterized by a t(14;18) translocation resulting in upregulation of BCL2 in over 80% of cases. This translocation alone is not sufficient for tumorogenesis, and must be combined with additional genetic mutations to transform B cells. FL is incurable and the disease course can be highly varied, with survival ranging from a few months to decades following diagnosis and treatment with standard chemoimmunotherapy. The heterogeneity of FL poses major challenges to identifying the association of genetic alterations and clinical outcome. Current WHO guidelines recommend establishing grade for each FL case with grade 3 thought to be more aggressive than 1 and 2. The genetic basis and clinical implications of grade in FL are unclear. Recent sequencing studies have identified many genes found to be recurrently mutated in FL including KMT2D and CREBBP. However, the degree to which genetic alterations cooperate with each other or contribute to clinical outcome is unclear. Based on the observed mutational rates in follicular lymphoma, we estimated 900 cases were needed to comprehensively delineate the genetic alterations that underlie histologic grade and clinical outcome. Accordingly, we enrolled a cohort of 1042 patients with newly diagnosed FL. All treated patients received rituximab-containing standard regimens. To go beyond the identification of gene-coding events, we developed a very large panel of 110 Mbp covering exonic (~40Mbp) and non-exonic regions (~70Mbp) of interest to enable a wide range of genomic analysis including mutation calling in both coding and non-coding regions, rearrangement detection, viral identification, and copy number analysis. In addition to the whole exome, we extended coverage to include introns, promoters, and untranslated regions of all known driver genes in cancer. We included the entirety of the immunoglobulin loci, T-cell receptor loci and CD3 loci to detect clonotypes and rearrangements. We also included lymphoma-relevant long non-coding RNAs, microRNAs, enhancers, and breakpoint-prone regions. For viral detection, we targeted the genomes of eight cancer-related viruses: Epstein-Barr virus, human papillomavirus, human immunodeficiency virus, hepatitis B, hepatitis C, Kaposi's sarcoma-associated herpesvirus, human T-lymphotropic virus, and Merkel cell polyomavirus. In addition, to enable high resolution identification of copy number variation (CNV) calls, the entire genome was tiled with probes spaced 10kb apart. DNA and RNA were extracted from all tumors and their paired normal samples, prepared into DNA and RNA sequencing libraries and subjected to sequencing on the Illumina platform to a targeted coverage of 150X. Somatic events were identified and further filtered to identify driver events in both coding and non-coding regions. FLs demonstrated a significant degree of genetic heterogeneity with over 100 genes mutated with a frequency of at least 2%. Nearly 100% of FL cases had a mutation in at least one chromatin-modifying gene. The most frequently mutated genes in follicular lymphoma were KMT2D, BCL2, IGLL5 and CREBBP. In addition, we identified frequent mutations in SPEN, BIRC6 and SETD2. To our knowledge, this is the first description of alterations in these genes in FL. Transcriptome analysis indicated a strong correlation between BIRC6 mutations and the previously described immune response 2 signature that is associated with a poor prognosis. We further performed unbiased clustering of genetic alterations in these FL cases. We identified a cluster that was specifically enriched in BCL6 and TP53 alterations and was strongly associated with grade 3 FLs which are predicted to have poorer outcomes with low intensity therapies. We further examined the genetic profiles of 1001 DLBCLs in comparison to this cohort of FLs. Our data indicate a continuum of highly overlapping genetic alterations with DLBCL displaying more complex patterns that included alterations in MYC, TP53 and CDKN2A (mainly copy number losses), indicating shared pathogenetic mechanisms underlying FL and DLBCL, particularly those germinal center B cell origin. Disclosures Koff: Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; Lymphoma Research Foundation: Research Funding; American Association for Cancer Research: Research Funding. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Gang:ROCHE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic & Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Flowers:AbbVie: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Neff:Enzyvant: Consultancy; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fedoriw:Alexion Pharmaceuticals: Other: Consultant and Speaker. Reddy:Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy; Abbvie: Consultancy. Mason:Sysmex: Honoraria. Behdad:Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Speaker. Burton:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dave:Data Driven Bioscience: Equity Ownership.

Abstract: Abstract 3407 Poster Board III-295 Background: Diffuse Large B Cell (DLBCL) is the most common histological subtype of lymphoma diagnosed in the United States. Following failure with standard Rituximab- CHOP chemotherapy, salvage therapy followed by autologous stem cell transplant is the standard treatment for those who are transplant eligible. Previous data suggest that early lymphocyte recovery is associated with superior survival after autologous stem cell transplantation (ASCT) in lymphoma. However, there are no consistent data on whether prior rituximab therapy affects lymphocyte recovery early post- transplantation. In this study we present our transplant outcome experience regarding early lymphocyte recovery in patients exposed to prior rituximab therapy. Methods: One hundred fifteen patients undergoing autologous stem cell transplant for relapsed DLBCL at a single institution between January 2000 and December 2008 were included in our analysis after obtaining IRB approval. Descriptive statistics, Wilcoxon signed rank sum test and Kaplan-Meier analysis were performed as required using SPSS software. Results: Median age of patients undergoing ASCT was 50 years (range: 24-69 years). Nine patients who underwent ASCT for transformed DLBCL and 7 patients with T-cell rich B cell lymphoma were also included in the final analysis. Six patients had stage I disease, 29 patients with stage II, 33 patients with stage III and 36 patients were diagnosed with stage IV. Thirteen patients had bulky retroperitoneal adenopathy at the time of original diagnosis. Seventy one (66.3%) patients received one salvage therapy prior to transplant. Thirty six (33.7%) patients received two or more salvage therapies prior to transplant. Mobilization data was available on 89 patients. Of those, 82 patients were mobilized with chemotherapy and 5 patients underwent mobilization with GCSF alone. High dose cytclophosphamide (7200 mg/sq.m), etoposide (2000 mg/sq.m) and BCNU (400 mg/sq.m) [CBV] was the conditioning regimen in 88 (77.2%) patients. Sixty eight (59.6%) patients received pretransplant rituximab therapy. Sixty one (61.6%) patients were in radiographic complete response (CR) following salvage therapy at the time of transplant. Sixty nine (78.4%) patients continued to be in CR at day 100 evaluation. Nineteen (21.6%) patients had persistent disease requiring further therapy. The median survival of all patients was 38.7 months (range: 3 months- 186 months). At the time of the analysis, 69 (60.5%) patients were still alive. Prior rituximab therapy did not affect lymphocyte recovery on day 14 (p=0.95) or day 28 (p=0.27). Lymphocyte recovery on day 14 and day 28 (continuous and categorical variables) had no impact on transplant outcome. Other factors such as age, disease stage at presentation, presence of bulky retroperitoneal nodal disease, number of regimens, mobilization procedure, type of conditioning regimen, pre-transplant radiation therapy, pre-transplant disease status (CR vs. PR in chemo sensitive disease) had no impact on survival. Conclusions: our data demonstrate that prior rituximab therapy has no impact on lymphocyte recovery on day 14 or day 28. In this group of patients, lymphocyte recovery did not impact on autologous stem cell transplant outcome. The survival benefit with early lymphocyte recovery as mentioned in prior reports may be lost with longer follow up. Prior rituximab therapy may mitigate the effect of the number of treatment regimens or disease status (CR vs. PR) on transplant outcome. Disclosures: No relevant conflicts of interest to declare.

Abstract: Introduction Diffuse large B cell lymphoma (DLBCL), the most common lymphoma world-wide, is strikingly heterogeneous. This heterogeneity creates a daunting challenge for conducting well-powered studies connecting molecular features to clinical outcome. Not only is the association of genetic mutations with clinical outcome in DLBCL mostly unknown, the relative importance of other well-described features, such as MYC and BCL2 translocation/expression and cell of origin based subsets (ABC and GCB DLBCL), is difficult to interpret due to conflicting reports. We sought to comprehensively define the spectrum of genetic mutations and their association with clinical outcome in DLBCL. Our calculations indicated that 500 tumor-normal pairs would provide 95% power to define mutations occurring in at least 5% of patients, and that 800 cases would be required to define the clinical correlations with cross-validation. Methods We enrolled 1001 de novo DLBCL patients, with complete IPI and survival data, who were treated uniformly with standard rituximab and anthracycline containing regimens. All tumors were subjected to whole exome and transcriptome sequencing (RNAseq), as well as SNP arrays to confirm genetic alterations. ABC (38%) and GCB DLBCL (36%) subtypes were defined using microarrays and RNAseq in these patients to examine subgroup-based differences in mutations and outcome. MYC and BCL2 expression were quantified separately. Results Gene discovery analysis of somatic mutations and copy number alterations in exome sequencing data from 502 tumor-normal pairs of DLBCL identified 197 recurrently mutated genes, including 155 genes previously identified to be mutated in DLBCLs. In addition, our study uncovered 42 novel driver genes in DLBCL (e.g. BTK, SPEN, CD70). Exome sequencing results were validated by Sanger sequencing of 1120 variants with over 90% concordance. We also identified copy number alterations in these genes, with strong agreement (90%) of amplifications and/or deletions to those detected on Illumina high resolution SNP microarrays. These 197 genes were found to comprise 15 functionally related subnetworks, including those related to histone modification, NFkB, B cell receptor, PI3K and cell cycle (Figure 1). Within each subnetwork, the vast majority of the gene alterations occurred in a mutually exclusive (P 〈 10-3) fashion in patterns consistent with their described functions within the subnetworks. For instance, among genes comprising the NFkB subnetwork, positive regulators of the pathway such as MYD88 and CARD11 showed activating patterns (copy number gains and recurrent hotspot mutations), whereas negative regulators such as TNFAIP3, NFKBIE, and NFKBIA were inactivated through genetic deletions or frequent nonsense or frameshift mutations. We examined the associations between the mutations and clinical outcome in all 1001 patients. All survival analyses were conducted using nearly equally split training and validation sets, corrected for multiple comparisons with significance of P 〈 0.01 in the validation set (Figure 2). The cell of origin classification was strongly associated with survival in our cases and was independent of MYC and BCL2 co-expression, which was separately associated with survival (Figure 2A). Figure 2B shows hazard ratios for select genes, as well as associated Kaplan-Meier survival curves for a subset of those genes. We further identified combinations of different genetic and expression features that point to context dependence for survival associations (Figure 2C). For instance, mutations in KLHL14 were associated with a particularly poor prognosis in ABC DLBCL, while CREBBP mutations in ABC DLBCL patients were associated with better prognosis than average GCB DLBCLs. Mutations in EZH2 and CD70 were associated with a highly favorable prognosis within the GCB DLBCL subgroup. TP53 mutations were found to be prognostic only in the presence of MLL2 mutations and high BCL2 expression. Importantly, these risk groups are mutually exclusive and inform clinical outcome significantly better than existing metrics. Conclusion To our knowledge, this is the largest whole exome sequencing study in any single cancer. Our study answers many long-standing questions in the disease, informing a comprehensive understanding of genetic drivers of DLBCL, their organization into pathways, and their relationship to clinical outcome. Disclosures Leppä: Roche: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda Pharmaceuticals: Consultancy, Honoraria, Other: Travel expenses; Janssen: Consultancy, Research Funding; CTI Bio Pharma: Consultancy; Mundipharma: Research Funding; Bayer: Other: Travel expenses, Research Funding. Flowers:ECOG: Research Funding; Gilead: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; TG Therapeutics: Research Funding; Mayo Clinic: Research Funding; NIH: Research Funding; Infinity: Research Funding; AbbVie: Research Funding; Genentech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Research Funding. Hsi:Seattle Genetics: Honoraria, Speakers Bureau; HTG Molecular Diagnostics: Consultancy, Honoraria; Eli Lilly: Research Funding; Cellerant Therapeutics: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Evens:Takeda: Other: Advisory board. Reddy:GILEAD: Membership on an entity's Board of Directors or advisory committees; INFINITY: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: It is known that patients with double hit (DHL) and triple hit lymphoma (THL) have a significantly worse prognosis compared to patients with diffuse large B-cell lymphoma (DLBCL) without MYC rearrangement (MYC-R). Some studies have shown that DLBCL patients with MYC rearrangement only (single hit lymphoma; SHL) also have a poor prognosis similar to those with DHL/THL. However, it is not uncommon for fluorescence in situ hybridization (FISH) to detect extra copies (EC) of MYC, BCL2 or BCL6 in the absence of rearrangement. The potential role of these extra copies (EC) on survival has not been fully explored. In the current study, we focused on the prognostic significance of MYC-EC in comparison with MYC-R in patients with de novo DLBCL treated with rituximab-chemotherapy. Materials and Methods: A total of 664 de novo DLBCL cases with MYC/8q24, BCL2/18q21 and BCL6/3q27status confirmed by FISH and/or karyotype from 2010-2015 were included. MYC SHL, DHL and THL were identified if they had rearrangements of MYC only, both MYC and BCL2 or BCL6, or concurrent MYC, BCL2, and BCL6, respectively. Positive expression for MYC or BCL2 by immunohistochemistry was defined by 〉 40% and 〉 50% staining in the lymphoma cells, respectively.Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test.Fisher's exact test was used to compare the clinicopathologic features.Statistical analysis was performed using SPSS 23 software. Results: 105 DLBCL had MYC-R, 77 had MYC-EC, and 482 had no MYC abnormality (MYC-NL). The 105 MYC-R cases included 28 SHL, 45 DHL (39 MYC/BCL2 and 6 MYC/BCL6 DHL), 11 THL, and 21 with unknown BCL2 or BCL6 status. Overall, the clinicopathologic features including overall survival (OS) were similar among SHL, DHL, and THL patients (Figure 1A, p=0.92). Patients with DLBCL harboring MYC-R had more aggressive clinicopathologic features than those with MYC-EC or MYC-NL (p 〈 0.05). There was no difference in the overall survival (OS) between patients with MYC amplification (≥5 copies) compared to those with 3-4 copies of MYC (p=0.41); as such; they were combined into to one group (designated MYC-EC) for further analysis. The features of patients with MYC-EC were largely similar to those with MYC-NL except a lower CR rate in MYC-EC group (57% vs 72% in MYC-NL, p=0.011). Although both the MYC-R and MYC-EC groups demonstrated a worse OS than MYC-NL patients (p 〈 0.01), the MYC-EC group had a trend towards a better OS when compared with the MYC-R group (p=0.086, Figure 1B). As expected, more patients received intensive induction chemotherapy (R-EPOCH & R-Hyper-CVAD) in the MYC-R group than in the MYC-EC or MYC-NL group (p 〈 0.01). Compared with R-CHOP, intensive induction chemotherapy showed only a trend towards better OS in the MYC-R and MYC-EC group (Figure 1C & 1D respectively). By multivariate analysis, MYC-R (HR=2.55, p=0.0001) but not MYC-EC was an independent prognostic factor in de novo DLBCL patients. Conclusion: Patients with DLBCL harboring extra copies of MYC have clinicopathologic features more in common to DLBCL patients with normal MYC status than those with MYC rearrangement. The OS in patients with DLBCL harboring extra copies of MYC was significantly worse than in DLBCL patients without MYC abnormality; however, it was not as poor as that seen in patients with DLBCL with MYC-R. Compared to R-CHOP, intensive induction regimens (R-EPOCH & R-Hyper-CVAD) showed only a trend towards better prognosis in DLBCL patients with MYC rearrangement or extra copies. Figure 1 Figure 1. Disclosures Westin: Chugai: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees. Reddy:GILEAD: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; INFINITY: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: DLBCLpatients (pts) with an elevated international prognostic index (IPI) score are at an increased risk of disease relapse rate in the first year after completion of standard therapy with rituximab (R) -CHOP. Lenalidomide (len), an immunomodulatory drug, has activity in relapsed DLBCL. Len enhances the natural killer cell mediated antibody-dependent cellular cytotoxicity of rituximab in lymphoma cell lines and inhibits angiogenesis as well as alters cytokine production. Given the activity of len in DLBCL, we explored this combination as a consolidative approach for one year following R-CHOP therapy. Methods: Intermediate-high/high risk IPI patients with DLBCL were randomized to len (arm A) alone or len and rituximab (arm B). The primary endpoint of the study was to assess the one year disease-free survival (DFS). We expected that a 25% difference of relapse from an expected 40% relapse based on historical controls would have clinical significance when compared with current standard therapy. Patients in arm A received len at a dose of 25 mg daily for 21 days of 28 days. Patients on arm B received len at a dose of 20 mg daily for 21 days of 28 days along with rituximab on day 8 of even cycles. Aspirin was administered to all patients. Treatment on both arms was continued for one year. Treatment was discontinued for disease progression. Len dose adjustments were incorporated in the protocol. Results: Forty-four pts, 22 arm A/ 22 arm B, 21 female/23 male, with a median age of 59.6 yrs (range 19-85 yrs) were enrolled. The median IPI was 4 for patients over the age of 60 and the median aa-IPI was 3. Three patients received radiation to areas of bulky disease. At a median follow-up of 3.64 years, the two-year DFS and overall survival (OS) was 86% (72%-94%) and 91% (77%-96%), respectively. For patients in arm A and arm B the two-year DFS was 86% (63% - 95%)% vs. 86% ( 62% - 95%)% (figure 1) and the two-year OS was 86% (62% - 95%)% vs. 95% ( 72% - 99%)% (figure 2), respectively (P=NS). Two pts discontinued treatment due to adverse events. The most common grade 3-4 toxicities include neutropenia (57%), fatigue (9%), diarrhea (8%), rash (1%). Related grade 1-2 toxicities include endocrine abnormalities [hypo/hyperthyroidism] (29.5%) and rash (65%). Conclusions: Len alone as maintenance therapy demonstrates significant clinical activity following standard chemotherapy and improves DFS and OS in DLBCL patients with high-risk prognostic features as compared with historical controls. This trial is registered with NCI- #NCT00765245 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Reddy: ImmunoGen: Consultancy; PCYC: Consultancy; Gilead: Other: Speaker; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding. Off Label Use: Lenalidomide following R-CHOP. Park:TEVA: Research Funding; Seattle Genetics: Research Funding; Jannsenn: Other: Travel.

Abstract: Introduction: MYC/BCL2 double hit lymphoma (DHL), defined as a large B-cell lymphoma with concurrent MYC and BCL2 translocations, is the most common type of DHL. Although multiple studies focused on DHL have been published, several issues regarding impact on prognosis remain controversial including: 1) history of low grade B cell lymphoma; 2) morphology (diffuse large B-cell lymphoma [DLBCL] versus B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma [BCLU)] ; 3) Absence or low expression of MYC or BCL2; 4) MYC translocation partner gene; and especially 5) most effective therapy. The aim of this study was to attempt clarify the prognostic importance of these factors in DHL. Methods: 157 patientsdiagnosed with MYC/BCL2 DHL between 2003 and April 2015 at two institutions were included in this study. MYC and BCL2 gene rearrangement were confirmed by FISH using a MYC breakapart probe and BCL2 and IGH dual color dual fusion probes. BCL6/3q27gene status was tested either by FISH using breakapart probe or by karyotype. MYC partner gene was identified by karyotype. MYC/BCL2 DHL cases were identified if they had rearrangements of MYC and BCL2 but not BCL6. Positive for MYC or BCL2 by immunohistochemistry was defined by 〉 40% and 〉 50% of lymphoma cells showed positive expression, respectively. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Fisher's exact test was used to compare the clinicopathologic features. Statistical analysis was performed using SPSS 23 software. Results: There were 103 men and 54 women with a median age of 61 years (range, 18-87). 110 patients had de novo disease and 47 patients had a history of low-grade B-cell NHL, mostly follicular lymphoma. The clinicopathologic features were similar (P 〉 0.05) between patients with a history of low-grade B-cell NHL and patients with de novo NHL, and therefore analysis was performed on all 157 DHL cases. Using the 2008 WHO classification, there were 91 DLBCL, 61 BCLU, and 5 composite lymphoma (4 DLBCL + follicular lymphoma and 1 DLBCL + B-lymphoblastic lymphoma). 99% of cases had a germinal center B-cell immunophenotype by the Hans algorithm. MYC expression was observed in 39/47 (83%) and BCL2 in 129/141(91%) of cases. MYC and BCL2 dual expression was present in 34/46(74%) cases. Of the 39 cases assessed, the MYC translocation partner was IGH in 13, IG light chain in 19, and a non-IG gene in 7 cases. 144 patients had complete treatment information: 61 received the R-CHOP regimen initially, 31 R-EPOCH, 29 R-HCVAD, and 23 various other chemotherapy regimens. 39 patients also received stem cell transplant (SCT) including 31 autologous and 8 allogeneic. 62 patients reached complete remission (CR) after initial chemotherapy. The median overall survival was 19 months. In a univariate analysis that evaluated 17 clinicopathologic parameters including those mentioned in introduction, extranodal sites of disease, bone marrow involvement, CNS involvement, advanced stage, and high/high-intermediate International Prognostic Index score were associated with a worse overall survival (OS, P 〈 0.05), whereas CR and SCT were associated with a better OS (P 〈 0.05). By multivariate analysis, stage, IPI, SCT, and CR predicted OS (Table 1 and Figure 1). Conclusion: MYC/BCL2 DHL are clinically aggressive B cell lymphomas with a germinal center phenotype and patients have a poor prognosis. In this study, a history of low grade B cell lymphoma, morphology (DLBCL vs BCLU), MYC expression, BCL2 expression, MYC/BCL2 dual expression (double expresser lymphoma), MYC translocation partner gene, and initial chemotherapy regimens were not associated with overall survival. The independent prognostic factors shown by multivariate analysis were IPI score, stage, achievement of CR, and a therapeutic regimen including SCT. Table 1. Multivariate analysis Features HR 95% CI P BM involvement 0.92 0.48 - 1.80 0.817 Extranodal sites ≥ 2 1.12 0.48 - 2.65 0.793 Stage III /IV vs I/II 34.45 4.92 - 241.31 〈 0.001 IPI (H/H-I vs L/L-I) 3.00 1.14 - 7.77 0.026 Initial Chemotherapy R-EPOCH vs R-CHOP 1.17 0.49 - 2.84 0.723 R-HCVAD vs R-CHOP 0.95 0.47 - 1.93 0.894 Stem cell transplant 0.22 0.10 - 0.46 〈 0.001 CR after initial chemotherapy 0.14 0.07 - 0.30 〈 0.001 Figure 1. Figure 1. Disclosures Reddy: ImmunoGen: Consultancy; PCYC: Consultancy; Gilead: Other: Speaker; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding.

Abstract: Double-hit (DH) diffuse large B cell lymphomas (DLBCL), characterized by concurrent translocations involving MYC and BCL2, or BCL6, portend to have an aggressive clinical course. Recent studies have highlighted the fact that DH lymphomas are resistant to standard R-CHOP or experience a short disease free interval. There is however limited data evaluating patient outcomes with alternative therapy that include aggressive regimens often used to treat high grade lymphoma. Methods Five hundred sixty patients (pts) diagnosed with DLBCL at a single institution between January 2004 and December 2012 were included in our analysis after obtaining IRB approval. Descriptive statistics, Wilcoxon signed rank sum test and Kaplan-Meier analysis were performed using SPSS.19 software. Results Of the 560 pts, 34 were confirmed as DH based on FISH analysis. The median age at diagnosis was 63 yrs (range 36-87). Twenty pts (59%) were male. Thirty-one pts (91%) were Caucasian. Fourteen pts (53%) had an Eastern Cooperative Oncology Group performance status of 2-3. Thirty pts (89%) had advanced stage disease (stages III and IV). Thirteen pts (38%) had bone marrow involvement, and twenty-six pts (76%) had more than one extranodal site. The majority of pts (70%) had high intermediate or high risk based on the International Prognostic Index (IPI). Of the 34 pts, 15 (46%) received R-CHOP, 6 (18%) received R-Hyper CVAD/Ara-C/MTX, 8 (24%) received DA-R-EPOCH and 2 (6%) received other aggressive forms of chemotherapy. Two pts died before any therapy was initiated. Ten pts (29%) received central nervous system prophylaxis. Five pts (15%) underwent stem cell transplant, 2 of which in CR1. Twenty-eight pts (82%) were alive at the time of analysis. At a median follow up of one year, the median overall survival (OS) of all pts was 12.2 months. The median OS was 16.8 months for pts who received R-CHOP and 12.2 months for pts receiving other aggressive chemotherapy (P=0.07) (figure 1). The progression free survival for pts who received R-CHOP was 32.6 months as compared with 7.6 months in pts treated with R-hyper CVAD/Ara-C/MTX or DA-R-EPOCH. This was not statistically significant (P=0.44) (figure 2). In addition, there was no significant difference in disease free interval between the two groups of patients. Conclusion Our data suggests that prognosis of patients with DH-DLBCL remains poor independently of the chemotherapy administered, whether conventional R-CHOP or more aggressive regimens such as R-HyperCVAD or DA-R-EPOCH. Durable long term remission with R-CHOP is still possible in a minority of patients. There is a need to modify and incorporate novel agents in the initial treatment strategy for DH-DLBCL. Disclosures: No relevant conflicts of interest to declare.