Thompson, Carrie A.

Abstract 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.

Abstract Abstract 1926 Background: Follicular lymphoma (FL) is the second most common non Hodgkin lymphoma in the United States, comprising up to 30% of all non Hodgkin lymphomas. Typically an indolent disease, relapses are common. High dose therapy followed by autologous stem cell transplant is an option that has shown to produce prolonged progression-free and relapse-free survival in patients who relapse. Adequate bone marrow reserve for peripheral stem cell mobilization has been shown to be adversely effected by prior regimens such as fludarabine and radioimmunotherapy. Concerns regarding stem cell mobilization at the point of relapse have led some to collect stem cells early in the course of disease to allow for potential subsequent transplant after relapse. Recent advances in stem cell mobilization have resulted in a 3% collection failure rate for lymphoma patients at the point of planned transplant at our institution versus a historical rate of up to 30%. We studied the utilization of stem cells collected for potential future use in FL patients in remission or prior to therapy at the point of relapse or progression in order to determine the utility of this approach. Methods: Record review of patients diagnosed with FL through the Mayo Clinic Tumor Registry and the Mayo Clinic Lymphoma Data Base who had cryopreserved stem cells for potential future transplant at relapse. Cost of stem cell storage at our institution was reviewed as was the subsequent use of the collected cells. Results: 73 patients with FL had stem cells collected and stored. 37 (51%) were collected prior to a double dose yttrium-90 (90Y) ibritumomab tiuxetan trial for relapsed lymphoma as required by the study. The median age at collection of this group was 56 years (range 28–70). Stem cells remain in storage for a median of 44 months (range 8–119). The median cost of cryopreservation and storage is $4,094 based on the median storage time of 44 months (range $3,628 to 5,065) with a collection cost of $3,524.20 and an annual storage fee of $155.39. This does not include the cost of filgrastim for mobilization, nor line placement. At 5 years, 60% of the cells were not utilized, and at 10 years, 56% of the cells were not utilized. 36 (49%) of the total number of patients were not part of the double dose 90Y ibritumomab tiuxetan trial, but were collected in remission for possible future use or in the setting of relapsed, progressed or transformed disease for potential future transplant. Five of these patients required the use of plerixafor for adequate mobilization. The median age at collection of this group was 47 years (range 24–76). Stem cells remain in storage for a median of 39 months (range 2–128). The median cost of cryopreservation and storage is $4,029 based on the median storage time of 39 months (range $3,550 to 5,182) with a collection cost of $3,524.20 and an annual storage fee of $155.39. This does not include the cost of filgrastim or plerixafor for mobilization, nor line placement. At 5 years, 89% of these cells were not used, and at 10 years, 71% of cells were not used. Conclusion: The utilization of stem cells collected early in the course of FL patients is low, with the majority of cells not being utilized at 10 years. Given improved mobilization techniques resulting in 97% efficacy of stem cell collection at relapse, routine collection and storage of stem cells early in the course FL is not recommended. Disclosures: Micallef: Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Abstract 4168 Background: Primary Pulmonary MALT lymphoma represents 15–20% of Extranodal Marginal Zone Lymphomas of Mucosa Associated Lymphoid Tissue (MALT). In contrast to the more common gastric MALT lymphoma, natural history, prognosis and treatment outcomes for primary pulmonary MALT lymphoma are not well defined. Herein, we report a single institution experience. Methods: Consecutive patients with primary pulmonary MALT lymphoma registered in the Mayo Clinic Lymphoma Database, which includes all consenting patients with lymphoma seen at Mayo Clinic Rochester, were reviewed for clinical features, treatment outcome progression free survival (PFS) and overall survival (OS). The pathology for all patients was centrally reviewed by hematopathologist and the diagnoses were based on WHO lymphoma classification criteria. PFS and OS were assessed using the Kaplan–Meier method and the Cox proportional hazard model was used to assess the impact of variables on PFS and OS. Results: Between December 1986 and June of 2009, ninety-seven patients with primary pulmonary MALT lymphoma were enrolled. The median age at diagnosis was 63 years (range 31–87). There were 43 (44%) males. The initial presentation was a unilateral pulmonary lesion (n=47, 48%), bilateral pulmonary lesions (n=41, 42%), and pulmonary lesion with intrathoracic lymphadenopathy (n= 4, 4%). Bone marrow involvement and presence of B symptoms were 4, 4% and 5, 5%, respectively. International Prognostic Index (IPI) was 0–1, 2–3 and 4–5 in 69, 25 and 1 patient(s) respectively. The median follow-up was 10.4 years. The estimated median OS was 13. 6 years and the median PFS was 5.5 years (Figure). In a multivariate analysis, age >60 (p=0.02) and ECOG PS>2 (p=0.01) were associated with shortened survival. The IPI and age adjusted IPI were not predictive of overall survival. The treatment outcomes for the most common treatment modalities are summarized in the Table below. The median PFS of the 38% of patients who had a complete surgical resection was excellent at 11.2 years; whereas for observed patients with residual disease after biopsy was 3.2 years. Only 8 patients received single agent rituximan with relatively low response rate. Summary: The prognosis of primary pulmonary MALT lymphoma is favorable, with a median survival of over 13 years. In patients with resectable disease, surgery alone is associated with excellent disease control. Further prospective studies are needed to define the optimal treatment of primary pulmonary MALT lymphoma. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2634 The peripheral blood absolute lymphocyte/monocyte ratio (ALC/AMC) at diagnosis has been recently reported [Porrata et al, Hematologica 2012; 97(2):262-9] and confirmed [Koh et al, Oncologist 2012; 17(6):871-80] to be a predictor of clinical outcomes in classical Hodgkin lymphoma (HL). In addition, an inversed correlation has been reported between the ALC/AMC ratio and tumor associated macrophages in classical HL suggesting an association between the host biological response in the macro-environment and micro-environment. However, a limitation of the ALC/AMC ratio at diagnosis, the International Prognostic Score at diagnosis, the Positron-Emission Tomography (PET-scan) at diagnosis, or interim PET-scan during treatment is their inability to sequentially assess the host/tumor interaction during treatment. Therefore, we studied the ALC/AMC ratio recovery, as a surrogate marker of host immunity (i.e., ALC) and tumor micro-environment (i.e., AMC), at each treatment cycle phase to assess its predictive ability for clinical outcomes in classical HL. To participate in the study, patients were required to be diagnosed, treated, and followed at Mayo Clinic, Rochester, Minnesota and treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiation therapy. An ALC/AMC ratio ≥ 1.1 cut-off was used in the study based on our previous publication [Porrata et al, Hematologica 2012; 97(2):262-9]. From 1990 until 2008, 190 classical HL patients qualified for the study. The cohort was evenly split with 50% males and 50% females. Fifty-eight percent of the patients had an interim PET-scan performed. The median age at diagnosis was 36 years (range: 18–83 years). Seventeen patients received 2 cycles; 5 patients 3 cycles; 51 patients 4 cycles; 5 patients 5 cycles and 112 patients 6 cycles. The median follow-up was 3.7 years (range: 0.2–20 years). The ALC/AMC ratio ≥ 1.1 at each treatment cycle phase of ABVD was a predictor for overall survival (OS), lymphoma-specific survival (LSS), progression-free survival (PFS) and time to progression (TTP). Patients were stratified based on how many cycles the ALC/AMC ratio did not reach the cut-off of 1.1. The more cycles with an ALC/AMC < 1.1 the worse survival was observed. The 23 patients who did not achieve an ALC/AMC ≥ 1.1 during the treatment cycles phase experienced the worst survival rates: 5 year OS of 33%; 5 year LSS of 43%; 5 year PFS of 16%; and 5 year TTP of 27%. Patients were then dichotomized into patients that did not achieve an ALC/AMC ratio ≥ 1.1 for all the cycles versus patients with an ALC/AMC ratio ≥ 1.1 in any cycle during treatment. Patients with an ALC/AMC ratio ≥ 1.1 in any cycle (N=167) experienced better survival compared with patients that in all cycles the ALC/AMC ratio was < 1.1 [ OS, the hazard ratio(HR) was 0.09, 95% CI (0.04–0.19), p < 0.0001; for LSS, HR =0.07, 95% CI (0.02–0.17), p <0.0001; for PFS, HR = 0.08, 95%CI (0.04–0.14), p < 0.0001; and for TTP, HR = 0.05, 95% CI (0.02–0.11), p < 0.0001]. In the multivariate analysis, an ALC/AMC ratio ≥ 1.1 in any cycle versus none was an independent predictor for clinical outcome when compared to ALC/AMC ratio at diagnsosis, PET-scan, International Prognostic Score, limited verus advanced stage, and radiation therapy [OS, HR = 0.14, 95% CI (0.04–0.40), p< 0.0002; for LSS, HR = 0.09, 95% CI (0.01–0.37), p <0.0006); for PFS, HR = 0.19, 95% CI (0.05–0.82), p < 0.03); and for TTP, HR = 0.15, 95% CI (0.02–0.89), p < 0.02]. In conclusion, the ALC/AMC ratio during ABVD treatment cycles in classical HL is a predictor for survival and provides an opportunity to develop therapeutic modalities to manipulate the ALC/AMC ratio during ABVD chemotherapy to improve clinical outcomes in classical HL. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 287 Purpose: Farnesyltransferases are key cellular enzymes involved in the prenylation of proteins. Prenylated proteins are important for malignant cell growth. The purpose of this phase II study (NCT00082888) was to assess tumor response and toxicity associated with the oral farnesyltransferase inhibitor tipifarnib (R115777, Johnson and Johnson) in patients with relapsed aggressive, indolent, or uncommon lymphoma. The uncommon group included low incidence lymphoma types such as Hodgkin lymphoma (HL) and T-cell non-Hodgkin lymphoma- cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Patients and Methods: Patients with relapsed or refractory non-Hodgkin (NHL) or Hodgkin (HL) were eligible if they had measurable disease, performance status ≤2, platelet count ≥75,000 × 10(6)/L, an absolute neutrophil count ≥1000 × 10(6)/L and a creatinine ≤2 × upper limit of normal. Patients initially received tipifarnib 300 mg twice daily, days 1–21 every 28 days. The trial was conducted by the University of Iowa/Mayo Clinic Lymphoma SPORE. Results: Ninety-three patients with lymphoma (42 aggressive, 15 indolent, and 36 uncommon) enrolled in the trial between March 2004 and November 2008. The median age was 62 years (range, 18–91). The median number of prior therapies was 5 (range, 1–17). The overall response rate (ORR) was 20% (19/93) with 6% (6/93) complete responses (CR) and 14% (13/93) partial responses (PR). The ORR was 17%, 7%, and 31% for the aggressive, indolent, and uncommon groups, respectively (Table). Among the 19 responders were 7 diffuse large B-cell lymphoma (DLBCL), 7 T-cell NHL, 1 follicular grade II, and 4 HL. The overall median response duration for the 19 responders was 7.5 months (mean, 12.8; range, 1.8 – 48.1 months). The median response duration was 11.3 months (mean, 10.1; range, 1.8 – 18.5 months), 2 months, and 7.5 months (mean, 15.5; range, 1.9 – 48.1 months) for the aggressive (7), indolent (1), and uncommon (11) groups, respectively. Five patients in the uncommon group are still receiving treatment with a range of treatment duration between 25 – 60+ months. Among the 5 still receiving treatment 4 responded and 1 is stable. The range of response duration is 15.4, 17.7, 43.1, and 48.1 months. These five patients (2 with HL, 1 anaplastic large cell cutaneous, and 2 PTCL) are currently receiving doses of 400 (1), 200 (2), and 100 (2) mg twice daily. The median time to progression for all patients was 3.6 months (95% CI: 2.1 – 4.5 months). The grade 3,4 toxicities observed were primarily fatigue (10%) and reversible myelosuppression with 11% anemia, 37% neutropenia, and 32% thrombocytopenia. Correlative studies demonstrated tipifarnib-induced upregulation of Bim, a marker of tipifarnib action in lymphoma cell lines, in 7 of 9 paired lymphoma biopsies. Conclusions: Tipifarnib has activity in lymphoma, with responses in patients with heavily pretreated DLBCL, HL and T-cell types, but little activity in follicular NHL. This agent has an excellent toxicity profile and targets a novel pathway. Further studies in combination with other agents are warranted for patients with DLBCL, HL or T-cell NHL. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Performance status (PS) is a measurement of a patient’s functional capabilities and has been validated as a prognostic indicator in patients with cancer. This study was conducted to compare patient and physician-rated Eastern Cooperative Oncology Group (ECOG) PS to determine the incidence of inter-observer variability and identify determinants of PS disagreement among a cohort of patients with hematologic malignancy. Methods Newly diagnosed patients with leukemia and lymphoma were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) from 2002-2008. At diagnosis, patients and their physicians were asked to independently rate ECOG PS. Those who reported PS within 1 month of diagnosis were included in this analysis. Chi-squared and Wilcoxon rank-sum tests were used to assess the association between PS disagreement and prognostic or demographic factors; Cox proportional hazards models and c-statistics were used to evaluate the association between PS and overall survival. Results 1269 patients were included with a median age of 61 years (range 18-91). Of these, 58% were male; 275 had chronic lymphocytic leukemia (CLL), 127 had Hodgkin lymphoma (HL), and 867 had non-Hodgkin lymphoma (NHL). Overall, 829 (65%) patients and physicians rated PS the same. Age greater than 60 was a significant predictor of disagreement overall (p<0.001), as well as in CLL (p=0.014) and NHL (p=0.004), but not in HL (p=0.65). We found that across disease subtypes, the level of disagreement increased with more aggressive disease. This finding was significant in those with HL (p=0.027) and NHL (p<0.0001) as International Prognostic Score (IPS) and International Prognostic Index (IPI) increased respectively. In CLL, the trend for Rai stage was suggestive but not statistically significant (p=0.27). The incidence of disagreement was highest among patients with NHL (37%), with a higher percentage of disagreement among those with aggressive (45%) vs. non-aggressive (25%) subtypes (p<0.001). Disagreement was lower in patients with CLL (27%) and HL (33%). There were no significant associations between patient gender or education level and PS rating among subtypes or overall. Patient and physician-rated PS were both significant predictors of overall survival in univariate models and also adjusted for subtype and subtype specific risk score. The prognostic ability for PS was similar for both patient rated and physician-rated assessment overall (c-statistic=0.76 for both patient and physician rated PS) and in those with HL (c-statistic=0.85 for both patient and physician rated PS) and NHL (c-statistic=0.76 for both patient and physician rated PS). However, patient-rated PS was better for prognostication in CLL (c-statistic=0.75; p<0.0001), compared to physician-rated PS (c-statistic=0.67; p=0.002). Conclusions Patients with hematological malignancies and their physicians do not always rate PS the same, particularly in patients who are older or have more advanced or aggressive disease. These findings suggest the need for physicians to communicate with patients when determining PS, as PS is a strong predictor of survival. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction Relapse in the central nervous system is an uncommon complication of diffuse large B cell lymphoma (DLBCL) associated with a poor prognosis. The addition of rituximab to chemotherapy has improved outcomes in patients with DLBCL but its effect on the outcome of patients with CNS relapse is not well characterized. Here we present the natural history of patients with CNS relapse in a large cohort of patients with DLBCL who were treated in the immunochemotherapy (IC) era. Methods Newly diagnosed patients with DLBCL or primary mediastinal B-cell lymphoma (PMBCL) and treated with primary anthracycline based IC were prospectively enrolled on the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis and followed for relapse, retreatment, and death. Clinical management at diagnosis and subsequent therapies were per treating physician. Patients with documented CNS involvement at diagnosis, primary CNS lymphoma, or post-transplant lymphoproliferative disorder at diagnosis were excluded. All CNS relapse and retreatment details were verified by medical record review. Results 1017 patients with newly diagnosed DLBCL or PMBCL, no documented CNS disease at diagnosis, and treated with IC were enrolled in the MER between 2002 and 2012. At a median follow-up of 59 months (range 1-148), 36 patients had CNS relapse. The cumulative incidence of CNS relapse was 3.1% (95% CI: 2.2%-4.4%) at 2 years and 3.7% (95% CI: 2.7%-5.0%) at 5 years after diagnosis. CNS involvement was identified after first line IC in 25 patients, and after salvage therapy in 11 patients. 22 patients had an isolated CNS relapse, while 14 had both systemic and CNS disease at relapse. The incidence of isolated CNS relapse at two years from diagnosis was 1.9% (95% CI: 1.2%-3.0%, figure 1). CNS involvement was parenchymal in 22 patients, leptomeningeal in 11, and parenchymal and leptomeningeal in 3 patients. At diagnosis, this subset of 36 patients had a median age of 61 years (range 20-86); 25 (69%) were male. IPI was 0-1 in 6 patients, 2 in 13 patients, 3 in 11 patients and 4-5 in 6 patients. Cell of origin per Hans algorithm was available in 17 patients, 8 were GCB and 9 were non-GCB. Extranodal sites of disease at diagnosis included testicular (2), renal (5), bone (10) and bone marrow (6). 7 patients had no sites of extranodal disease. LDH was elevated in 71%. The German High-Grade Non-Hodgkin Lymphoma Study Group CNS risk score was low risk in 6 patients, intermediate risk in 22 patients, and high risk in 8 patients. 6 patients received CNS prophylaxis with their initial immunochemotherapy, including 3 of the 21 patients who subsequently developed isolated CNS disease. First line therapy after CNS relapse included high dose methotrexate based chemotherapy in 22 patients and other systemic regimens in 6, with intrathecal (IT) chemotherapy in 5. Overall survival in patients after CNS relapse was poor with a median survival of 6.3 months (95% CI: 2.9-15.5) and 12-month survival rate of 29% (95% CI: 17%-49%). Patients who had CNS relapse following initial IC had better subsequent survival (median OS = 7.6 months) compared to patients with first presentation of CNS relapse following salvage therapy (OS = 2.1 months, p=0.005, see figure 2). 10 patients (28%) proceeded to SCT after CNS relapse, of which 6 remain alive at a median follow-up of 39 months. There were no differences in post-CNS relapse survival by age, sex, CNS risk score, cell of origin, extranodal site involvement at diagnosis, or site of CNS relapse (all p>0.10), though power was limited due to small numbers. Conclusions The incidence of CNS relapse in DLBCL is approximately 4% in the immunochemotherapy era. The vast majority of CNS relapses occur within 2 years of diagnosis. Isolated relapse in patients without CNS involvement at diagnosis is a relatively rare event with an incidence of approximately 2% at 2 years of diagnosis. Outcomes remain poor, and standard clinical variables do not predict survival after CNS relapse. Novel therapeutic approaches are needed in this population, with consideration to autologous SCT, which produces durable remission in a subset of patients. Disclosures Maurer: Kite Pharma: Research Funding. Farooq:Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Cerhan:Kite Pharma: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding.

Abstract Small lymphocytic lymphoma (SLL) is an incurable indolent lymphoma, and there are relatively few prognostic biomarkers for this important NHL subtype. We evaluated the hypothesis that inherited variability in cytokine and immune-related genes was associated with overall survival in SLL. We genotyped 73 SNPs in 44 candidate genes in 140 SLL patients aged 20–70 years who participated in a population-based case-control study conducted from 1998–2000 through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Detroit, Seattle, Iowa, and Los Angeles. DNA was extracted from a venous blood sample or mouthwash buccal cell sample. All genotyping was conducted at the National Cancer Institute Core Genotyping Facility using the Taqman platform. Histology, stage, presence of B-symptoms, first course of therapy, date of last follow-up, and vital status were derived from linkage to registry databases at each study site in the spring of 2005. Cox proportional hazards analysis was used to estimate the hazard ratio (HR) and 95% confidence interval for the association between individual SNPs and overall survival, adjusted for age, demographic and clinical factors. Multiple simultaneous modeling strategies were used to identify the best summary multi-SNP risk score to predict survival. At last follow-up, there were 45 deaths in 140 patients (32%). The median follow-up of the 95 surviving patients was 58 months (range 24–75 months). In multivariate modeling, SNPs in IL13 (rs1800925; HRCC=2.36, 1.24–4.49), IL7R (rs1494555; HRGG =2.20, 0.84–5.76), and TNF-alpha (rs1800630; HRAC/AA=1.73, 0.95–3.17) were the strongest and most robust predictors of survival. Two or more deleterious genotypes from these three SNPs increased the risk of death (HR=2.2, 1.2–4.1) compared with one or fewer deleterious genotypes (p=0.009). Three groups (low, intermediate, and high risk) were defined by combining the SNP score and a clinical/demographic score. The 5-year Kaplan-Meier survival estimates for these groups were 85%, 65%, and 11%, respectively. Compared to patients with a low risk score, patients with intermediate (HR=2.5, 1.2–5.1) or high (HR=11, 4.3–27.7) risk scores had poorer overall survival (p=3.9 x 10−8). Our preliminary results suggest that SNPs in IL13, IL7R, and TNF-alpha alone and in combination predict overall survival in SLL, lending support to the hypothesis that host genetic background is a promising class of prognostic biomarkers in SLL.

Abstract Abstract 1540 Background: Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoma in the western world. Outcomes have improved with the standard initial therapy of rituximab and anthracyline based chemotherapy (immunochemotherapy). However, 20–40% of patients will either fail to achieve remission or relapse following initial immunochemotherapy. Most relapses occur early, and long-term outcome of relapsed/refractory patients is generally poor despite salvage regimens and stem cell transplant. Traditionally, studies for DLBCL have been evaluated using progression-free and/or overall survival. However, the event rate in DLBCL slows significantly approximately 12–18 months after diagnosis, and late events are often due to competing (non-DLBCL related) risks, especially in older patients. Here we examine outcome of DLBCL patients based on their event status at 12 months. Methods: Newly diagnosed DLBCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER). Clinical data were abstracted from medical records using a standard protocol. Patients were actively followed for events (progression, re-treatment, or death due to any cause) and overall survival (OS). Event-free status at 12 months after diagnosis (EFS12) was assessed as a dichotomous variable. Cause of death was determined by medical record and death certificate review using prospectively determined definitions. Expected survival was based on age and sex matched survival using the Minnesota population death rates. Confirmation cohorts were from a Lyon, France hospital based registry and NCCTG clinical trial N0489. Results: 680 patients with newly diagnosed DLBCL and treated with rituximab + anthracycline based chemotherapy were enrolled in the MER from 2002 to 2009. The median age was 62 years (range 18–92). 53% were male. At a median follow-up of 59 months (range 8–116), 266 patients (39%) had an event and 188 patients (28%) died. 162 patients (24%) had an event in the first 12 months after diagnosis, comprising 60% of all events. Patients with an event in the first 12 months had poor survival with death almost exclusively due to disease (Figures 1a, 2a). In contrast, patients who were event-free at 12 months had comparable survival to the age and sex matched general population (Figure 2b) and were more likely to die of other causes than DLBCL (Figure 1b). Overall survival rates by EFS12 status were validated in patients from a French hospital-based registry (N=265) and the NCCTG N0489 clinical trial (N=87) with additional replication studies underway. Conclusions: DLBCL patients who are event-free at 12 months after diagnosis have an excellent prognosis with an overall survival similar to that of an age- and sex- matched general population and are more likely to die of other causes than DLBCL. This finding has implications for clinical management, new clinical trials, and follow-up testing in this patient population. In contrast, patients with an event within the first 12 months after diagnosis have a poor prognosis with almost all deaths secondary to DLBCL. EFS status at 12 months identifies patients with poor outcomes due to disease. This can be utilized as an endpoint in biologic studies and clinical trials to address early treatment failures. EFS status at 12 months should be incorporated into prognostic models to identify high risk patients in newly diagnosed DLBCL. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1604 Background EBV (+) DLBCL of the elderly is a lymphoproliferative disorder recently included as a provisional entity in the 2008 WHO classification of lymphoid tumors. Defined as EBV (+) DLBCL in patients over the age of 50 years without known immunosuppression, information is evolving in this entity. To date, the true incidence of EBV (+) DLBCL in adults remains imprecisely determined and may vary regionally. This study sought to determine the incidence, presenting clinical characteristics, and outcome of EBV (+) in an unselected cohort of DLBCL patients enrolled in a prospective observational study. Methods The University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) is a prospective, longitudinal observational study designed to collect information on patterns of care and outcomes for patients with newly diagnosed lymphoma. Patients seen at the Mayo Clinic, Rochester MN and the University of Iowa within 9 months of their initial diagnosis of lymphoma are offered enrollment. HIV (+) patients are excluded. Baseline patient reported data, clinical data and initial management are collected using a standard protocol and a central pathology review is performed. After enrollment, patients are actively followed for events (disease progression, retreatment, and death) and disease related comorbidities. Tissue Micro Arrays (TMA) are constructed on available primary biopsy specimens. Epstein Barr Encoded RNA (EBER) EBV testing was performed by in-situ hybridization, and scored by an expert hematopathologist. EBER reactivity in more than 30% of malignant cells were required for EBV(+) designation. All DLBCL patients from the MER with available TMA excluding primary mediastinal DLBCL and post transplant lymphoproliferative disorders (PTLD) are included in the current analysis. Event free survival (EFS) was defined as time from diagnosis until recurrence, retreatment, or death due to any cause. Results 184 newly diagnosed DLBCL patients with available TMAs were enrolled in the MER from 2002–2009. The median age at enrollment was 62 (range 18–89) and 57% were male. 89.7% were treated with immunochemotherapy. At a median follow-up of 66 months (range 1–116), 80 patients (43%) had an event which included 59(32%) deaths. TMA testing was positive for EBV in 13 (7 %) samples with an even distribution among age groups. There was a trend toward higher percentage of stage III/IV disease (85 vs 57%, p = 0.052), and BM involvement (46 vs 16%). EBV (+) was not associated with other extranodal disease or further identifiable differences in presenting clinical characteristics. Controlling for IPI, the hazard ratio for EFS among EBV+ in DLBCL pts over 50 was 0.41 (95% CI = 0.13–1.32) p = 0.14. EFS and OS curves for pts over 50 are shown below. There were no events or deaths in the 4 EBV+ pts under age 50. Conclusions EBV+ DLBCL represents a small proportion of DLBCL patients presenting for care to our academic medical centers, consistent with reports from other regions. Substantial unique clinical characteristics at presentation for those pts with EBV+ disease were not identified, and outcomes were no worse than EBV (−) counterparts. Given the apparent regional differences in reports of EBV(+) DLBCL of the elderly, future clinical series will need to establish a more precise definition or determine more distinctive features to justify adoption of EBV(+) DLBCL of the elderly as a full entity in the WHO classification. Disclosures: No relevant conflicts of interest to declare.