ALBERT

Description: Network coding has been confirmed as a potential technology to improve performance of wireless mesh networks (WMNs); network coding has great advantages for sensor networks like minimization of communication needed to collect sensor data and error recovery. A few network coding aware routings have been proposed. However, these mechanisms detect coding opportunities through local traffic pattern checking, which hardly obtains optimal routes. This paper proposes a Distributed Dynamic Memetic Algorithm Based Coding Aware Routing (DDMCAR) for wireless mesh networks, which employs memetic algorithm to optimize routes and coding opportunities. This paper proposes an improvement over GCAR algorithm by employing memetic algorithm and also meme sharing among nodes to increase the chance of finding optimal solution and continuous monitoring and update of meme fitness to achieve a dynamic tracking of network conditions, and finally using most fit memes for load balancing elevating congestion. Through simulations on randomly generated wireless mesh networks, DDMCAR is to be shown to find optimal routes within a short time and achieve more improvements than GCAR.

Description: With recent advances in wireless sensor networks and embedded computing technologies, body sensor networks (BSNs) have become practically feasible. BSNs consist of a number of sensor nodes located and deployed over the human body. These sensors continuously gather vital sign data of the body area to be used in various intelligent systems in smart environments. This paper presents an intelligent design of the body sensor network based on virtual hypercube structure backbone termed as Smart BodyNet. The main purpose of the Smart BodyNet is to provide resilience for the BSN operation and reduce power consumption. Various experiments were carried out to show the performance of the Smart BodyNet design as compared to the state-of-the-art approaches.

Description: Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p

Description: Background The introduction of Imatinib therapy has significantly changed the treatment of patients with newly diagnosed chronic myeloid leukemia (CML) and improved survival. Since the International Randomized Study of Interferon (IRIS), a number of studies were conducted involving diverse populations and showed significant variations in the treatment outcome. To date, there has been no published study on the effectiveness of imatinib in adult CML patients in Saudi Arabia. The aim of the present study was to present a single-institution experience in the treatment with imatinib of newly diagnosed patients with CML and compare it with results from international studies. Methods A total of 101 medical records of consecutive adult CML patients treated with imatinib as first line therapy at King Abdulaziz Medical City, Jeddah, Saudi Arabia between 2001 and 2012 were retrospectively reviewed. Survival and response rates were evaluated. Results The estimated overall survival (OS) rates at 5 and 10 years were 95%±2.3% when patients were stratified by cytogenetic type (stander vs.variant Ph positive chromosome) at presentations, significant difference in OS, EFS, and PFS were noted (P=0.001). Complete haematological response was achieved in 94 (93.1%) of our patients, cytogenetic response (CR) in 84 (83.2%) while complete and major cytogenetic response (MCR) were observed in 70 (69.3%) and 6 (5.9%) of the patients respectively. (MR), 62 patients (61.4%) achieved major molecular response (MMR) and 34 (33.7%) complete molecular response. Conclusion compared to other studies among different population, our results confirm the previously noted variation in the response to imatinib. Our study has shown that Ph variant has an impact on the outcome. Further study may be indicated. However second TKI generations as first line in treatment CML with Ph variants should be consider! Disclosures: No relevant conflicts of interest to declare.

Description: Anti-PD-1 monoclonal antibodies have shown promising results in several hematologic malignancies. As a result, these agents are being tested in a growing number of clinical trials across multiple diseases and settings. Many participants in these trials will at some point become candidates for allogeneic hematopoietic stem cell transplant (HSCT); however, the safety and efficacy of HSCT may differ in patients previously exposed to PD-1 inhibitors given their immunomodulatory mechanism and long tissue half-life. Specifically, residual PD-1 inhibition post-HSCT could enhance allogeneic T-cell responses, which could augment the graft-vs-tumor (GVT) effect but also increase the incidence, severity or manifestations of graft-vs-host disease (GVHD) and other immune complications of HSCT. To report our experience in this setting, we retrospectively analyzed the outcomes of patients who had received a PD-1 inhibitor prior to HSCT. Between 2013 and 2015, 19 patients who previously participated in clinical trials with either pembrolizumab or nivolumab (administered in combination with ipilimumab in 1 patient) were transplanted at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Median age at HSCT was 32 (range 22-67). Histologies included HL (n=11), DLBCL (n=2), FL (n=2), PMBCL (n=2), EATL (n=1), and MCL (n=1). Patients had received a median of 4 (2-8) lines of therapy prior to PD-1 blockade. 79% of patients had received a previous autologous stem cell transplant (21% as part of planned tandem procedure). Patients received a median of 8 (3-20) cycles of a PD-1 inhibitor; 74% had intervening salvage therapy between PD-1 blockade and HSCT, and transplant occurred a median of 130 (range 7-260) days after the last dose of PD-1 inhibitor. At HSCT, 63% of the patients were in CR and 16% had refractory disease. All patients received reduced intensity conditioning (RIC). 5 (26%) received marrow grafts from haploidentical sibling donors; the remaining 14 received peripheral blood stem cells, 5 from a matched sibling, 7 from a matched, 1 from a unidirectional host-versus-graft and 1 from a bidirectional mismatched unrelated donor. 3 cases of veno-occlusive disease (VOD) (16% of patients) were observed, one of them fatal. The 180-day cumulative incidences of grade 2-4 and grade 3-4 acute GVHD were 32% and 11%, respectively, and the 1-year cumulative incidence of chronic GVHD was 30%. There were 4 treatment-related deaths, (1 from VOD, 3 from severe acute GVHD occurring within 14 days of HSCT). In addition, 6 patients developed a febrile syndrome with elevated transaminases (n=3), rash (n= 4), and arthralgias (n=1) shortly after transplant, which required prolonged courses of steroids. Only 3 patients relapsed. After a median follow-up of 10 (3-23) months for survivors, the 1-year overall (OS) and progression-free survivals (PFS) were 78% (95CI, 52-91) and 67% (95CI, 41-84), respectively (Figure). The 1-year cumulative incidences of relapse and non-relapse mortality (NRM) were 11% (95CI, 2-30) and 22% (95CI, 6-43), respectively. In conclusion, HSCT is feasible in patients previously treated with PD-1 inhibitors, with acceptable PFS and OS. Despite the heterogeneous patient population, small sample size, and limited follow-up to date, our results raise the possibility of important differences in the post-HSCT course of those patients. First, the relapse rate compares favorably to that expected for this cohort (1-year expected relapse rate based on Disease Risk Index mix 28%). Although this finding is at best suggestive given the sample size and follow-up time, it could reflect accentuation of GVT by prior PD-1 blockade. We also observed a high rate of severe complications including fatal early acute GVHD and VOD, with a higher NRM than expected in a RIC HSCT population. Furthermore, we noted the frequent occurrence of a steroid-responsive febrile syndrome. These possible effects of prior PD-1 blockade (including GVHD, VOD, febrile syndrome) did not appear related to the time from PD-1 treatment to HSCT, and were not reduced by intervening treatment before HSCT. As we accumulate experience with HSCT after PD-1 blockade, our early results may be relevant when considering the decision to proceed to HSCT and for the choice of transplantation strategies. We are presently expanding this analysis through a multi-center international collaborative study. Updated results will be presented at the meeting. Figure 1. Figure 1. Disclosures Zinzani: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perales:Takeda: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Merck: Honoraria; NMDP: Membership on an entity's Board of Directors or advisory committees. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Armand:Sequenta, Inc.: Research Funding; Merck: Consultancy, Research Funding; Infinity: Consultancy, Research Funding; BMS: Research Funding.

Description: Spliceosomal mutations account for the most frequent class of mutations in patients with MDS and CMML, yet the mechanism by which these mutations perform their driver function is not well understood. Moreover, no genetically engineered murine models for expression of spliceosomal gene mutations from their endogenous loci have been reported. Given the genetic heterogeneity of primary patient samples, we generated a model for conditional expression of the commonly occurring SRSF2P95H mutation from the endogenous murine locus of Srsf2. We compared expression of the Srsf2P95H mutation with genetic inactivation of 0, 1 or 2 copies of Srsf2 to understand the biological and mechanistic consequences of spliceosomal mutations relative to loss-of-function. Mx1-cre Srsf2P95H/wildtype mice exhibited significant morphologic dysplasia, leukopenia, macrocytic anemia, and preserved bone marrow (BM) cellularity as early as 2 weeks after mutation expression (Figure A). Moreover, Mx1-cre Srsf2P95H/wildtype mice exhibited an increase in hematopoietic stem/progenitor cells (HSPCs) with an increase in lineage-negative Sca1+ c-Kit+ cells (LSK cells) in S-phase and early apoptosis. In competitive transplantation, Srsf2P95H mice HPSCs were expanded in the BM at 16 weeks post-transplantation despite having a reduced contribution to peripheral blood chimerism. In contrast, mice with homozygous deletion of Srsf2 exhibited anemia and leukopenia due to BM aplasia with striking loss of HSPCs (Figure B). Collectively, these data show that Srsf2 is required for hematopoiesis, while mutations in Srsf2 provide a competitive advantage at the level of HSPCs but impair differentiation into mature circulating blood elements. Next, to identify transcriptional and post-transcriptional alterations caused by SRSF2 mutations, we performed deep RNA-seq on sorted HSPC populations from wildtype and Srsf2P95H mice, stable K562 cell lines ectopically expressing an empty vector or a single allele of SRSF2 (WT, P95H, P95L, P95R), as well as primary CMML and AML patient samples. We quantified global changes in splicing of ~125,000 alternative splicing events and ~160,000 constitutive splice junctions associated with SRSF2 mutations in these datasets. Intersection of differentially spliced genes in primary murine HSPC, CMML, and AML samples identified 75 genes that were differentially spliced in association with SRSF2 mutations in murine HSPCs and at least one primary patient cohort. Many of the genes that were differentially spliced in SRSF2 mutant cells participate in biological processes of known importance in myeloid malignancies. For example, a cassette exon of EZH2 that alters the reading frame likely to induce nonsense-mediated decay was promoted by SRSF2 mutations, while a frame-preserving cassette exon of BCOR was repressed by SRSF2 mutations. We next sought to determine how SRSF2 mutations alter SRSF2Õs normal role in RNA splicing. As SRSF2 recognizes exonic splicing enhancer (ESE) elements within the pre-mRNA to promote exon recognition, we hypothesized that SRSF2 mutations might alter its normal sequence-specific activity. To test this, we performed an ab initio motif identification screen to identify motifs that were enriched or depleted in cassette exons promoted versus repressed in primary Srsf2P95H cells relative to wildtype. This analysis identified CCAG and GGTG as the most enriched and depleted consensus motifs, respectively. A recent solution structure of SRSF2 in complex with RNA revealed that SRSF2 normally recognizes the motifs CCNG and GGNG equally well. Analysis of the spatial distribution of CCNG and GGNG motifs across genomic loci containing cassette exons that were promoted or repressed in association with SRSF2 mutations revealed that CCNG and GGNG were respectively enriched and depleted specifically over the cassette exons, and not over the flanking introns or exons, that were differentially spliced in association with SRSF2 mutations (Figure C). Together, our data indicate that mutant SRSF2 drives widespread changes in splicing due to alterations in its sequence-specific recognition of exonic splicing enhancers. The biological as well as molecular data here identify an effect of the SRSF2P95H mutation distinct from haploinsufficient or complete loss of SRSF2 and reveal that mutations in SRSF2 alter ESE preference to contribute to key aspects of MDS. Figure 1 Figure 1. Disclosures Feala: H3 Biomedicine: Employment. Buonamici:H3 Biomedicine: Employment. Smith:H3 Biomedicine: Employment.

Description: Mutations affecting the spliceosomal protein U2AF1 are among the most common mutations observed in patients with MDS and related disorders. However, it is unclear how these mutations affect the normal RNA splicing process, and how the resulting changes in splicing contribute to myeloid dysplasia. Here, we combined the strengths of data from primary AML patient samples with the controlled context of isogenic cell lines. We generated K562 erythroleukemic cell lines stably expressing each of the four common U2AF1 mutations (S34F, S34Y, Q157P, and Q157R). We compared expression of each of these mutant alleles with knock down of endogenous U2AF1 to compare the relative consequences of U2AF1 mutations versus loss of function. We first sought to identify changes in splicing driven by U2AF1 mutations that contribute to myeloid dysplasia. We compared the splicing of ~125,000 annotated alternative splicing events and ~160,000 constitutively spliced junctions between AML samples with or without mutations (TCGA cohort), as well as our isogenic K562 cell lines stably expressing either mutant (S34F, S34Y, Q157P, and Q157R) or wild-type (WT) alleles of U2AF1. Unsupervised cluster analysis revealed that S34F/Y versus Q157P/R samples clustered together in both the AML data and our cell lines, suggesting that U2AF1 mutations affecting different residues of the protein have different molecular consequences. Intersecting the AML and K562 data, we identified 〉300 splicing events that were consistently differentially spliced in association with S34 mutations, and a similar number for Q157 mutations. Many of these splicing events affected biological pathways that have been implicated in myeloid malignancies, including DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), the DNA damage response (ATR, FANCA), and apoptosis (CASP8). For example, two exons of DNMT3B are differentially spliced in both AML samples and our K562 cells (Figure A), including an exon lying within the methyltransferase domain. We next identified mechanistic changes in the splicing process caused by U2AF1 mutations. U2AF1 binds the intron-exon boundary by sequence-specifically recognizing the AG dinucleotide and flanking sequence positions that define the 3' splice site. Comparing AML samples and K562 cells with and without U2AF1 mutations, we found that S34 and Q157 mutations give rise to specific and distinct alterations in 3' splice site preference. S34 mutations alter the consensus nucleotide immediately before the AG dinucleotide, while Q157 mutations alter the consensus nucleotide immediately after the AG (Figure B). We observed highly similar allele-specific alterations in 3' splice site preference in every AML patient with a U2AF1 mutation, as well as all K562 cell lines expressing a U2AF1 mutant allele. In contrast, knock down of endogenous U2AF1 caused no alterations in the consensus sequence at those positions, indicating that U2AF1 mutations do not cause loss of function at the level of RNA splicing. To confirm that the nucleotides immediately before and after the AG determine whether a splice site responds to U2AF1 mutations, we created minigenes of cassette exons within the ATR and EPB49 genes. We found that response to U2AF1 S34 and Q157 mutations requires the endogenous nucleotides immediately before and after the AG, as predicted by our genomics analysis, and that mutating these positions abolishes response to U2AF1 mutations. Finally, we recapitulated the RNA splicing process in vitro using nuclear extract from blood cells expressing either wild-type or mutant U2AF1 to show that identical changes in splice site preference occur in a controlled in vitro context (Figure C). Together, our data show that U2AF1 mutations cause allele-specific alterations in normal 3' splice site recognition in patients, in isogenic cell lines, and in vitro. These alterations in splice site preference give rise to mis-splicing that affects many genes previously implicated in myeloid malignancies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Background: Follicular lymphoma (FL) is the most common indolent Non-Hodgkin lymphoma. Diagnosed with advanced disease, most patients have an excellent prognosis, but treatment options are not curative and can have significant morbidity. To date, there is no standard of care for first-line (1L) treatment for FL. In fact, current National Comprehensive Care Network (NCCN) guidelines list 11 (including three category 1) 1L treatment options for FL. Following the successful completion of 1L treatment, patients may also receive consolidation or maintenance rituximab (MR) therapy, with the intent of prolonging remission. Although MR has been shown to improve progression free survival, its impact on overall survival (OS) remains controversial. Leveraging electronic healthcare records, we identify and describe the demographics, treatment practices, and associated outcomes of FL patients diagnosed and treated in the nation's largest integrated healthcare system, the Veterans Health Administration (VHA), Methods: FL patients diagnosed and treated in the VHA between 2006-2014 were identified by linking information from the VA Clinical Cancer Registry (VACCR) and the Corporate Data Warehouse (CDW). Patients were excluded if they had evidence of a prior cancer, documented grade 3b, or stage I disease. Patient demographics, disease characteristics, and treatment history and associated outcomes were extracted. Patients were grouped by 1L treatment(s) which included rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP); rituximab, cyclophosphamide, vincristine, and prednisone (RCVP); bendamustine rituximab (BR), single-agent rituximab; and whether or not they received MR. Descriptive statistics were used to describe patient demographics, disease characteristics, and treatment practice patterns. Proportions were used for discrete variables; means and/or medians (with standard deviation or interquartile range, respectively) were used to describe continuous variables. Overall survival (OS) was compared between patients who received MR and those who did not, using an adjusted Cox proportional hazards model. Results: From 2006-2014, 2290 FL patients were diagnosed at VHA, from all regions of the United States. Median age was 65 years, 95% were male, 81% were non-Hispanic white, 7% were black, 2% were Hispanic, and 8% were other/unknown. At diagnosis, 25% of patients were grade 1, 27% grade 2, and 12% grade 3, and 4% were documented as grade 1-2. More than half (58%) of these patients had disease at stage III or IV at diagnosis, with 13% at stage II, and 21% at stage I. The most common comorbidity was diabetes, present in 27% of patients, followed by pulmonary disease (18%), peripheral vascular disease (8%), and renal disease (8%). Overall, 793 (85%) patients were treated with chemoimmunotherapy, with 341 (15%) patients receiving RCHOP, 253 (11%) receiving RCVP, and 199 (9%) receiving BR; while 132 (6%) patients were treated with single-agent rituximab. Compared to patients treated with chemoimmunotherapy, patients treated with single-agent rituximab were significantly older (77% ≥ 60 vs 67%, p=0.022) and less likely to have elevated LDH (14% vs 24%, p=0.03) or grade 3 disease (9% vs 21%, p= 0.002). Of the 905 patients who were treated with chemoimmunotherapy or single-agent rituximab and showed no evidence of progressive disease (i.e., MR-eligible patients), 319 patients (35%) received MR. On multivariable analysis, the following were independently associated with decreased OS: age at treatment ≥ 60 (HR=2.1, p=0. 0.0003), hemoglobin 〈 12 g/L (HR=1.5, p=0.041), LDH 〉 ULN (HR=1.6, p=0.013), and Charlson comorbidity index (CCI) ≥ 2 (HR=1.1, p=0.05). Accounting for immortal time bias, MR was associated with a significant improvement in OS (HR = 0.7, p = 0.04). Conclusions: This nationwide real-world study yields detailed information and new insights into current FL patient characteristics, treatment practices, and associated outcomes. Rituximab maintenance was independently associated with an improvement in overall survival in patients with FL. Disclosures Halwani: Takeda: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Miragen: Research Funding; Kyowa Hakko Kirin: Research Funding; Immune Design: Research Funding; Genentech, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Abbvie: Research Funding. Masaquel:Genentech: Employment, Equity Ownership; Roche: Equity Ownership. Henderson:Genentech/Roche: Employment, Equity Ownership. Delong-Sieg:Roche: Equity Ownership; Genentech, Inc.: Employment. Sauer:Amgen: Research Funding; COHRDATA: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding.

Description: Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive Non-Hodgkin lymphoma, with approximately one third of patients not responding (or relapsing) after receiving first-line (1L) therapy, typically a multi-agent chemoimmunotherapy regimen containing rituximab and doxorubicin. These patients may be treated with a second-line (2L) chemotherapy (CT) or chemoimmunotherapy (CIT) regimen, with the intention to proceed to a high-dose therapy followed by an autologous stem cell transplant (SCT). Unfortunately, a significant proportion of older patients are unable to tolerate such treatment. There is little data on treatment practices and outcomes in older DLBCL patients receiving 2L CT or CIT after failure of 1L therapy. Using electronic healthcare record data from the largest integrated health system in the United States, the Veterans Health Administration (VHA), we examined real-world outcomes of DLBCL patients ≥ 65 years of age receiving 2L CT or CIT following 1L therapy with rituximab and doxorubicin containing regimens. Methods: DLBCL patients diagnosed from 2001-2015 and treated at the VHA were identified by linking information from the VA Clinical Registry System (VACRS) in the VHA Corporate Data Warehouse (CDW) to administrative, laboratory and pharmacy data, and clinical notes in the CDW. Patients were included in the analysis if they: had no evidence of a prior malignancy, were diagnosed with DLBCL, received 1L therapy containing rituximab and doxorubicin for ≥ 21 days, then subsequently received a 2L CT or CIT, and were ≥ 65 years of age at time of 2L treatment. Patient age, gender, race/ethnicity; stage at diagnosis, lactate dehydrogenase (LDH), and Charlson Comorbidity Index (CCI) were extracted from VACRS and/or CDW. Patients were censored at end of study observation period (Dec 31, 2016) or if a second cancer diagnosis occurred following their DLBCL diagnosis. Patients were divided into 2 groups: Group 1 included patients receiving a 2L regimen that, per the National Comprehensive Cancer Network (NCCN) guidelines, is typically used with intention to proceed to high-dose therapy; Group 2 included patients receiving a regimen that, per NCCN, is used in non-candidates for high-dose therapy. Receipt of SCT was identified using ICD codes and/or clinical notes. Results: 230 DLBCL patients met our inclusion criteria. Of these, 223 (97%) were male and 171 (74%) were of non-Hispanic, white ethnicity. Baseline characteristics (at time of 1L) were as follows: 156 (68%) had stage III-IV disease, 154 (67%) had LDH 〉 ULN, and median CCI was 4 (IQR:2-5). The majority of patients (217, 94%) received RCHOP as 1L, with the remaining receiving RCHOP + etoposide (13, 6%). Two thirds of patients, (151, 66%) started 2L within 1 year of starting 1L with a median of 10.6 months between start of 1L and start of 2L. Patients were almost equally divided between the two groups, with Group 1 (109, 47%) and Group 2 (121, 53%). Of the 109 Group 1 patients, 68 (62%) received ifosfamide, carboplatin, etoposide (ICE) +/- rituximab (R), and 22 (20%) received etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP) +/- R. Of the 109 Group 1 patients, 14 (13%) proceeded to SCT within VHA (SCT outside VHA was not extracted for this study). The remaining 121 Group 2 patients received 2L therapy with the following: bendamustine (B) +/- R (28, 23%), gemcitabine, oxaliplatin (Gem-Ox) +/- R (21, 17%), cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) +/- R (17, 14%), cyclophosphamide, etoposide, vincristine, prednisone (CEOP) +/- R (14, 12%), cyclophosphamide, etoposide, prednisone, procarbazine (CEPP) +/- R (12, 10%); CHOP + etoposide +/- R (6%), lenalidomide +/- R (6%). Fewer than 10 of these patients proceeded to SCT. The median OS of all patients was 8 months. Conclusions: This is the first study that details treatment practices and outcomes in a nationwide cohort of older adult patients (≥ 65 years old) with relapsed/refractory DLBCL. Approximately half of these older patients did not receive or were not candidates for regimens typically used with intent for high-dose therapy and autologous transplant. OS for the entire cohort was less than a year. Despite significant advances in available treatments for DLBCL, there remains an unmet need in treatment of relapsed/refractory DLBCL, especially in older patients who have difficulty tolerating high-dose regimens. Disclosures Halwani: Takeda: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Miragen: Research Funding; Kyowa Hakko Kirin: Research Funding; Immune Design: Research Funding; Genentech, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Abbvie: Research Funding. Schulz:Genentech: Employment, Equity Ownership; Roche: Equity Ownership. Li:Roche: Equity Ownership; Genentech: Employment. Masaquel:Genentech: Employment, Equity Ownership; Roche: Equity Ownership. Halloran:Genentech, Inc.: Employment, Equity Ownership; Janssen Pharmaceuticals, Inc: Employment, Equity Ownership. Delong-Sieg:Roche: Equity Ownership; Genentech, Inc.: Employment. Sauer:Genentech: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; COHRDATA: Research Funding; Amgen: Research Funding.

Description: Background: Nearly 40% of patients with diffuse large B-cell lymphoma (DLBCL) are either refractory to or relapse (R/R) after initial first-line (L1) treatment. These patients frequently receive subsequent lines of treatment, although to achieve long-term remission requires aggressive chemoimmunotherapy followed by autologous bone marrow transplant (BMT). Few real-world studies have examined the treatments used in R/R DLBCL patients over the entire disease trajectory. Methods: Using the VA Cancer Registry System and electronic healthcare records (EHR), we identified Veterans diagnosed with DLBCL between January 1, 2000 to December 31, 2016 who relapsed or progressed after L1 RCHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone ± rituximab) ± etoposide and then proceeded to receive at least one additional line of treatment. Human annotation of EHR notes confirmed DLBCL diagnosis, treatment regimen(s) received (including BMT), and treating physician response assessment after each line. Treatment regimens were classified as aggressive (with intent to proceed to BMT) or non-aggressive per National Comprehensive Cancer Network (NCCN) guidelines. Eligible patients were followed until loss to follow-up, death or the end of the study period (March 31, 2019). Patients with a cancer diagnosis other than DLBCL were excluded from the study. Results: We identified 270 R/R DLBCL patients who received a second-line (L2) treatment after having previously received L1 with RCHOP ± etoposide. The mean age of patients was 64.6 years; 97.4% of patients were male. Of the 270 patients, 166 (61.5%) patients received an aggressive L2 treatment regimen. RICE (ifosfamide, carboplatin, and etoposide ± rituximab) and BR (bendamustine ± rituximab) were the most commonly used aggressive and non-aggressive regimens, accounting for 39.3% and 8.9% of L2 treatment, respectively. Compared with patients who received non-aggressive L2 treatment, aggressive L2 treatment patients were younger (61.4 versus 69.7 years). Following aggressive L2 treatment, 87 patients (52.4%) achieved complete or partial response (CR/PR), while CR/PR was achieved in 43 (41.3%) patients who received non-aggressive L2. Of the 29 (10.7%) patients who received BMT, 28 received an aggressive L2 regimen. Approximately half of all patients who received L2 therapy (121/270) proceeded to third-line (L3) treatment, of which 47 (38.8%) received an aggressive L3 regimen. Nearly half of those patients who received an aggressive L2 treatment (36, 47.4%) proceeded to an aggressive L3 regimen, while only 11 (18.8%) non-aggressive L2 patients proceeded to aggressive L3 treatment. Following L3 treatment, 7 (5.8%) patients proceeded to a BMT. The median overall survival (OS) in patients receiving L2 was 9.7 months (CI: 8.2-11.7 months). The median OS for patients treated with aggressive L2 was 9.7 months (CI: 8.1-12.2 months) compared with 9.7 months (CI: 6.8-12.9 months) in patients treated with a non-aggressive L2. The median progression-free survival (PFS) for patients treated with aggressive L2 was 5.6 months (CI: 4.6-7.9 months) and 4.9 months (CI: 3.5-8.4 months) for patients treated with non-aggressive L2. Median OS in patients receiving L3 was 6.3 months (CI: 5.1-8.7 months). The median OS for patients treated with aggressive L3 was 6.8 months (CI: 5.1-12.5 months) compared with 6.6 months (CI: 4.8-9.7 months) in patients treated with a non-aggressive L3. The median PFS for patients treated with aggressive L3 was 4.5 months (CI: 2.6-6.9 months) and 2.9 months (CI: 1.8-5.7 months) for patients treated with non-aggressive L3. Conclusions: Patients who receive aggressive L2 treatment tend to be younger, more likely to receive another aggressive therapy (if L3 treatment is needed), and were much more likely to proceed to BMT than patients who received non-aggressive L2 therapy. Patients who received aggressive L2 treatments resulted in higher response rates compared to less aggressive treatment. We did not find a difference in OS between patients who received aggressive and non-aggressive treatment, the cause of which may be multifactorial. Future studies will examine factors that may impact OS in these patient groups. Acknowledgments: The study was sponsored by Genentech, Inc. Masaquel, Halloran, DeLong-Sieg, Schulz, and Li are employees of Genentech and may receive stock options from Roche. Disclosures Halwani: Pharmacyclics: Research Funding; Immune Design: Research Funding; Seattle Genetics: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Kyowa Hakko Kirin: Research Funding; Miragen: Research Funding; Genentech, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding. Masaquel:Roche: Equity Ownership; Genentech: Employment. Halloran:Genentech, Inc.: Employment; Roche: Equity Ownership. Delong-Sieg:Genentech/Roche: Employment, Equity Ownership. Schulz:Roche: Equity Ownership; Genentech, Inc.: Employment. Li:Genentech: Employment; Roche: Equity Ownership. Sauer:University of Utah and SLC VA Medical Center: Employment.