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Abstract Relatively little is known about the quality of life (QOL) status among long-term (5–20 year) lymphoma survivors. Using the Mayo Tumor Registry, we identified eligible patients who were 16 years or older at diagnosis, U.S. residents, first diagnosed with Hodgkin or non-Hodgkin lymphoma from 1984–1998, diagnosed and/or initially treated at Mayo Clinic Rochester, and survived for 5 to 20 years (N=2,485). In October of 2004, we mailed a 23-page survey to 95 randomly selected patients; 7 were found to be ineligible (deceased or too ill). Of the 88 remaining patients, we were able to find a correct address for 82, and 57 completed a survey for a 70% participation rate. QOL assessments included the Functional Assessment of Cancer Therapy - General (FACT-G), and a series of linear analogue self-assessment (LASA) single-item QOL measures. Results for the pilot sample were compared to normative data for each measure relating to general cancer patient populations. All scores were transformed onto a 0–100 point scale (higher score meaning higher functioning) for ease of comparison. Of the 54 patients with complete data for analysis, the mean age at survey was 60.8 years (6.3–19.9). The mean time since diagnosis was 12.0 years (6.3–19.9), and 52% had survived more than 11 years. The mean total score for the FACT-G was 89 compared to a norm of 74 for cancer patients. Higher scores were also seen in the lymphoma survivors in each of the four FACT-G subdomains (physical, social/family, emotional and functional well-being) compared to normative cancer patient populations. The global LASA QOL measure was also higher among lymphoma survivors (mean score of 82 compared to a norm of 77), and only 7% reported a global QOL score of 50 or lower, indicative of impaired QOL. Functioning among the lymphoma survivors was higher compared to general cancer patients on the mental, physical, emotional, social, pain, fatigue, financial, and legal LASA items, while functioning was similar to general cancer patients on the spiritual and support LASA items. However, scores suggestive of impaired QOL were reported by more than 10% of the patients for the social (17%), pain frequency (31%), fatigue (20%), and financial concerns (25%) items of the LASA. There were suggestive results of effect sizes indicating that smokers had lower FACT-G physical and emotional scores, and lower LASA mental and physical QOL scores, although none achieved statistical significance. In conclusion, this pilot sample of long-term lymphoma survivor patients reported having high QOL on most domains of the FACT-G and LASA relative to other cancer patient populations. There appears to be a subset of patients who experience impaired QOL and who may require further interventions, particularly in the QOL domains of social, pain, fatigue, and financial functioning. These results also suggest that awareness of smoking status may be important. Further larger studies are needed to confirm these preliminary data and to evaluate other aspects of QOL.

Abstract Patients during cancer treatment and cancer survivors frequently utilize complementary and alternative medicine (CAM) therapies. While the beliefs and knowledge regarding CAM of many cancer-specific patient groups have been well studied such as breast cancer patients and prostate cancer patients, no specific evaluation of lymphoma survivors and their beliefs and knowledge about CAM has been undertaken. Because CAM can yield both risks such as toxicity and displacement of efficacious therapy as well as potential benefits such as improvement in quality of life and mood, we surveyed lymphoma survivors in a pilot study to ascertain their current beliefs, knowledge, and utilization of CAM. Using the Mayo Tumor Registry, we identified eligible patients who were 16 years or older at diagnosis, U.S. residents, first diagnosed with Hodgkin or non-Hodgkin lymphoma from 1984–1998, diagnosed and/or initially treated at Mayo Clinic Rochester, and survived for 5 to 20 years (N=2,485). In October of 2004, we mailed a 23-page survey to 95 randomly selected patients; 7 were found to be ineligible (deceased or too ill). Of the 88 remaining patients, we were able to find a correct address for 82, and 57 completed a survey for a 70% participation rate. Complete data were available on 54 patients at the time of this analysis. The mean age at completion of the questionnaire was 60.8 years (26.1–86.7). The mean time since diagnosis was 12.0 years (6.3–19.9), and 52% survived more than 11 years. The histologies included 22 (39%) Hodgkin lymphoma, 21 (38%) diffuse large B-cell, 3 (5%) follicular, 1 (1%) high grade, 5 (9%) peripheral T-cell lymphoma, and 4 (7%) other. A majority of patients expressed no knowledge about the use of CAM cancer care, while only 4% of patients responded that CAM could both cure cancer and that it was perfectly safe. Ten to twenty percent of patients felt that CAM could assist other therapeutic interventions, relieve symptoms, assist the body to heal or increase quality of life. Fifteen percent of patients reported that CAM utilization increased the feeling of control, and 24% reported that CAM could have side effects. With respect to CAM utilization, overall 32% of patients had ever used CAM, but no patients reported that CAM usage was directed specifically towards their lymphoma. The most commonly used CAM modalities were chiropractic (39%), massage (21%), relaxation therapy (7%), meditation (5%) and acupuncture (5%). Overall usage of dietary supplements was relatively low, with green tea, garlic, flax seed, and echinacea being the only dietary supplements used by more than 10% of respondents. Five percent had used St. John’s Wort and 7% had used shark cartilage. In conclusion, lymphoma long-term survivors appear to use CAM at a rate similar to the general population, which does not follow the typical pattern seen in other cancer survivorship populations. The use of St. John’s Wort has potential risks if not identified prospectively. At the same time, lack of access to potentially beneficial modalities was also identified, and these observations suggest the opportunity for further study of targeted educational interventions regarding the use of CAM in this population.

Abstract Background: DLBCL without an event (disease progression, retreatment or death) within 24 months post diagnosis have a subsequent overall survival equivalent to that of the age- and sex-matched general population. In contrast, patients with an event with 24 months post diagnosis have poor survival. Patients experiencing early events are a heterogeneous group, consisting of patients with primary refectory disease and responding patients who later developed relapse. While the outcome of patients with primary refractory disease have been recently studied, little is known about or patients who have a response following immunochemotherapy (IC) and proceed to surveillance. These patients are the subject of recently completed and ongoing post-IC maintenance trials. To provide perspective, we analyzed outcomes of patients from a prospective observational study entering post IC. Methods: Newly diagnosed patients with DLBCL and treated with anthracycline-based immunochemotherapy were enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) from 2002-2009. End of immunochemotherapy (EOIC) was defined as the date the patient entered surveillance after completion of anthracycline-based IC as per our previous study of surveillance imaging. Response status at EOIC was abstracted as reported from the clinical and radiographic (CT and/or PET) reports. EFS24 was defined being event-free at 24 months from diagnosis, where events consisted of progression, re-treatment, or death (any cause) after initial immunochemotherapy. Survival from EOIC was compared to the general United States population using standardized mortality ratios (SMR) and expected survival. Logistic regression with EFS24 as the endpoint was used to identify pretreatment variables that inform prognosis at the time of EOIC, using Odds ratios (ORs) and 95% confidence intervals (CI) as the measure of association. A subset analysis was performed in the patients aged 60-80 with aaIPI 1-3. Results: 680 patients with DLBCL were enrolled in the MER and initiated R-CHOP or comparable IC from 2002-2009. 552 pts (81%) completed therapy and proceeded to surveillance. Median age of the 552 patients was 61 years (range 18-92) and 51% were male. At a median FU of 89 months from EOIC (range 5-156), 146 pts (26%) had died, and 467 (86%) achieved EFS24. From EOIC, the 5 year overall survival was 82% compared to 91% expected based on age and sex matched general population; SMR was 1.88 (95% CI: 1.60-2.22). In the patients age 60-80 with aaIP1 1-3, (N=203), 79% achieved EFS24 and the 5-year OS from EOIC was 75% compared to 89% expected; SMR was 2.08 (95% 1.65-2.61). When examining all 552 patients proceeding to surveillance at end of EOIC, several high-risk disease characteristics at diagnosis were associated with higher risk of failing EFS24 after completion of therapy: ECOG PS 2-4 (OR = 2.72, 95% CI: 1.55-4.78) , LDH> ULN (OR = 3.54, 95% CI: 1.99-6.31), Stage III/IV (OR=2.43, 95% CI: 1.41-4.16), and aaIPI (per-point OR = 2.02, 95% CI: 1.54-2.64). Patients reported to be in CR at EOIC were more likely to achieve EFS24 (90%) compared to patients not in CR (72%, p<0.001). Conclusion: Patients entering surveillance after IC have shortened overall survival when compared with the general US population, with significant proportion of patients having an event within 24 months of diagnosis. Increased aaIPI and response less than CR are risk factors for inferior EFS24 in this group. Assessment of the prognostic value of EOIC response (PR vs. CR based on central review) is ongoing. Disclosures Nowakowski: Celgene: Research Funding; Morphosys: Research Funding; Bayer: Consultancy, Research Funding. Maurer:Celgene: Research Funding; Kite Pharma: Research Funding. Howlett:Celgene: Employment, Equity Ownership. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Abstract Background: There are a number of ongoing clinical trials assessing next-generation immunochemotherapy (IC) regimens (i.e. RX-CHOP) in DLBCL. In addition to standard clinical trial workup, some trials require central pathology review and/or molecular phenotyping before treatment assignment and/or initiation of therapy. There is concern that these studies may be biasing patient selection due to missing patients with aggressive disease who require immediate therapy and cannot delay their treatment to enroll on a study. Here we examine clinical characteristics and outcome stratified by the time from diagnosis to initiation of therapy from a large observational cohort of patients with DLBCL from the R-CHOP era. Methods: Patients were prospectively enrolled in 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. This analysis includes patients with stage II-IV DLBCL or primary mediastinal B-cell lymphoma (PMBCL) who underwent front-line anthracycline based IC; patients with primary CNS lymphoma, PTLD, or a component of low-grade lymphoma were excluded. Time from diagnosis to treatment was defined as the time from date of first lymphoma-containing biopsy to the initiation of IC therapy; delayed therapy was defined as initiating therapy more than 14 days after diagnosis. Event-free survival was defined as time from diagnosis until progression, retreatment, or death due to any cause. EFS24 was defined as progression free status 24 months from diagnosis. Results: 720 patients with stage II-IV newly diagnosed DLBCL or PMBCL and treated with IC were enrolled in the MER from 2002-2012. Median age at diagnosis was 62 years (range 18-92) and 399 patients (55%) were male. 541 patients (75%) had stage III/IV disease and IPI at diagnosis was 0-1 in 166 patients (23%), 2 in 221 patients (31%), 3 in 222 patients (31%) and 4-5 in 111 patients (15%). 233 of 395 patients (59%) were GCB per Hans. At a median follow-up of 73 months, (range 0-163), 349 (49%) patients had an event and 267 patients died (37%); 37% of patients failed to achieve EFS24. Median time from initial lymphoma diagnosis to initiation of IC was 14 days (range 0-79, IQR=8-23). Patients with delay in therapy (>14 days from diagnosis) were more frequently female (50%, p=0.0051) and older than patients who initiated therapy within 14 days from diagnosis (median age at diagnosis of 63 years vs. 60 years, p=0.0008). Patients with delay in treatment initiation had universally less aggressive disease characteristics, including earlier stage, non-elevated LDH, 0-1 extranodal sites, absence of B-symptoms, lower ECOG PS, and lower IPI (see table). In addition, patients with delayed therapy were enriched for GCB subtype per Hans algorithm (p=0.056). Patients with initiation of therapy within 14 day of diagnosis had significantly worse outcome (EFS24 failure=44%) compared to patients with delayed time to initiation of therapy (EFS24 failure=28%, p<0.0001, figure), which remained significant after adjusting for either IPI or aaIPI (both p<0.005). The association between delayed time to initiation of therapy and EFS24 was observed in both GCB (EFS24 failure = 42% vs. 27%, p=0.019) and non-GCB (EFS24 failure = 46% vs. 27%, p=0.014) subsets by Hans. The lower event rate in delayed therapy patients results in an approximately 10% loss of power if the study was powered based on all patients regardless of timing from diagnosis to therapy. Conclusions: Patients with delayed therapy from diagnosis have less aggressive clinical characteristics compared to patients who initiate treatment within 14 days from diagnosis. Studies with a lengthy trial work-up including central pathology review period may be selecting patients with less aggressive disease based on the patient's ability to delay treatment to complete study enrollment requirements. Furthermore, selection of patients with less aggressive disease may result in underpowered studies due to a lower event rate (fewer events) than expected. This retrospective analysis would suggest that trials in DLBCL should consider streamlined enrollment and therapy initiation to avoid potential selection bias and loss of power. Further assessment of implications on trial design and outcomes by cell of origin in this setting is ongoing. Table Table. Figure Figure. Disclosures Maurer: Kite Pharma: Research Funding; Celgene: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Nowakowski:Morphosys: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Research Funding.

Abstract Background: B-cell lymphomas with a MYC/8q24 rearrangement coupled with translocations involving BCL2 and/or BCL6, often referred to as double hit or triple hit (DH/TH) lymphomas, typically have an aggressive clinical course. A new WHO subtype, "high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements", has been established for this entity (Swerdlow et al. Blood; 127: 2375-2390, 2016). Herein we report the treatment and outcomes of DH/TH patients at our institution. Materials and Methods: Cases were identified through the Mayo Clinic Lymphoma Database, University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), and the Mayo Clinic Cytogenetics Laboratory. Interphase FISH was performed clinically on either paraffin sections of the tissue specimens or on smears of the bone marrow aspirate specimens using break-apart probes for MYC and BCL6, dual fusion probes for IGH/MYC, IGL/MYC, and IGK/MYC, and either a BCL2 break-apart probe or an IGH/BCL2 dual fusion probe. Consensus pathology re-review was performed to define morphology as diffuse large B-cell lymphoma (DLBCL) vs. high-grade B-cell lymphoma (HGBCL). Patients with de-novo DH/TH or diagnosis of DH/TH at the time of transformation of a previously diagnosed low-grade lymphoma and who were treated with anthracycline-based chemotherapy were included in this analysis. Patients with DH/TH first identified at the time of recurrent aggressive B-cell lymphoma were excluded. Overall survival (OS) was defined as time from DH/TH diagnosis to death from any cause. EFS12 was defined as event-free status 12 months from diagnosis of DH/TH. Results: Clinical outcome analysis was performed on 71 patients (Table 1). The median age was 61 years (range 29-82). 60 patients had de-novo DH/TH and 11 patients had transformation of a previously diagnosed low-grade lymphoma. In 65 cases in which there was consensus morphology on pathology re-review, there were 39 (60%) with HGBCL morphology and 26 (40%) with DLBCL morphology. At a median follow-up of 21 months (range 1-87), the event free survival at 12 months was 43%, and the median overall survival (OS) was 22 months (95% CI: 13-NA). The OS at 5 years was 48% (95% CI: 36%-63%). Patients with DH/TH at transformation of previously diagnosed low-grade lymphoma had a very poor outcome (median OS=10.8 months, EFS12 = 10%), which was inferior to patients with de-novo DH/TH (P=0.0069). When compared to all other therapies, patients treated with R-CODOX-M/IVAC had better EFS12 (p=0.03) with a trend in improved OS (p=0.08) though this may be confounded by patient selection bias as these patients were significantly younger (p=0.0001) than patients treated with other anthracycline based regimens (table 1). Conclusion: In "high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements", induction failure occurs early. Although transformation to DH/TH from previously diagnosed low-grade lymphoma is associated with a particularly poor outcome, the overall survival for the entire cohort at 5 years was 48%, suggesting long-term cures in a subset of patients. Treatment with R-CODOX-M/IVAC may result in superior outcomes in patients less than 60 years of age. Table 1 Table 1. Figure Figure. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Nowakowski:Celgene: Research Funding; Morphosys: Research Funding; Bayer: Consultancy, Research Funding.

Abstract Background: Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of relatively uncommon and generally aggressive non-Hodgkin lymphomas. Recent studies have begun to reveal their mutational landscape, such as the recurrent mutations affecting RHOA, IDH2, and TET2 in angioimmunoblastic T-cell lymphomas (AITLs) and related PTCLs. Here, we studied the exomes of 63 PTCLs to address several unanswered questions: (1) How frequently do PTCLs have mutations with a strong rationale for being actionable using clinically available targeted therapies? (2) What pathways are enriched in PTCLs that could point to additional targeted therapies? (3) What additional recurrent mutations exist that may provide insight into PTCL pathogenesis and classification? Methods: We performed exome capture and sequencing in 63 frozen PTCL samples (with matched germline controls from 22), including 13 PTCLs, not otherwise specified; 6 AITLs; 37 anaplastic large cell lymphomas (ALCLs: 12 ALK+, 19 ALK-, and 6 cutaneous); 4 extranodal NK/T-cell lymphomas; 2 cutaneous T-cell lymphomas, and 1 enteropathy associated T-cell lymphoma. Following primary variant calling, data were filtered by removing variants that were: outside the capture region, polymorphic (0.1% in ExAC), seen in paired germline or 50 healthy controls, within repetitive elements, or synonymous. Potentially actionable variants required published evidence for altering protein function and demonstrated in vivo or in vitro sensitivity to an available targeted agent (including open clinical trials). Mutated cancer genes (COSMIC) were examined for enrichment of KEGG canonical signaling pathways. A recurrent mutation encoding MSC E116K was validated in tumor DNA and MSC protein was examined by immunohistochemistry. Results: Of 25 unique variants with published evidence suggesting actionability (including ErbB, JAK/STAT, and RAS genes), at least one variant was present in 16/63 patients (25%). Variants in any COSMIC gene were seen in 55/63 samples (87%). Top genes were STAT3, RHOA, ARID1A, MLL2 (KMT2D), PTPRB, TP53, and TET2. The KEGG ErbB pathway was most significantly enriched for mutated genes in our dataset (EGFR, ERBB2, ERBB3, ERBB4, and others; q=3.88x10-3), followed by neurotrophin and mitogen-activated protein kinase signaling pathways. Among 25 recurrent non-synonymous variants, we identified MSC E116K with predicted gain-of-function exclusively in 3 ALK-ALCLs and 1 cutaneous ALCL. All mutated cases strongly expressed MSC protein. Among 96 cases, 13/18 ALK-ALCLs (72%) were positive for MSC, compared to 9/78 (12%) from other PTCL subtypes. Conclusions: Mutations that were potentially actionable based on published variant-specific data were identified in 25% of PTCLs, indicating promise for the role of sequencing in individualizing therapy. Additionally, remaining variants were enriched for several targetable pathways, most significantly ErbB. A novel recurrent mutation, MSC E116K, was seen exclusively in ALK-ALCLs (systemic and cutaneous). MSC protein, a repressor of E2A-mediated transcription of targets such as MYC, was expressed in most ALK- ALCLs and generally was absent in other PTCL subtypes. This finding extends evidence for a genetic relationship between systemic and cutaneous ALCLs and suggests MSC may help distinguish ALK- ALCLs from other PTCLs. Disclosures Link: Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding.

Abstract Background. The incidence of non-Hodgkin lymphoma (NHL) has increased dramatically since at least the 1950s, and only a fraction of this increase can be explained by established risk factors. During this timeframe, there has been a major increase in the use of blood transfusions, anesthesia, and invasive surgical procedures, all of which can impact immune function. Methods. We conducted a population-based case-control study from 1998–2000 using SEER cancer registries in Detroit, Iowa, Los Angeles and Seattle. NHL cases (N=759) were newly diagnosed, HIV-negative, and aged 20–74 years. Controls (N=589) were identified through random digit dialing (<65 years old) and Medicare files (age 65 years and older), and were frequency matched to cases on sex, age, race, and study site. Data on history of blood transfusions, anesthetics (general and regional), and surgeries (type, frequency, and age for 21 anatomic regions) >1 year before diagnosis (or date of enrollment for controls) were collected during in-person interviews. Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI), adjusted for the matching factors. NHL subtypes (follicular and diffuse) were designated according to SEER cancer registry pathology reports, and risk of each subtype was estimated using polychotomous logistic regression. Results. History of blood transfusion was weakly associated with increased risk of NHL (OR=1.26; 95% CI 0.91–1.73), and the elevated risk was specific to transfusions first given 5 to 29 years before diagnosis (OR=1.69; 95% CI 1.08–2.62). Risk was also specific to blood transfusions given for a medical indication (OR=2.09; 95% CI 1.03–4.26), while transfusions given for trauma, obstetric or surgical indications were not associated with risk. Exposure to general or regional anesthesia (OR=1.35 for 24+ times compared to 0–6; 95% CI 0.91–2.02) and total number of surgeries (OR=1.22 for 7+ surgeries compared to 0; 95% CI 0.77–1.93) were weakly and positively associated with risk of NHL, although neither association achieved statistical significance. Results were similar for general versus regional anesthesia. In analysis of surgeries at specific anatomic sites, there were no associations with NHL risk, except for a suggestive positive association for surgery involving the appendix, stomach or bowel (OR=1.24; 95% CI 0.98–1.58). When blood transfusion, anesthesia, and total number of surgeries were included in the same model, ORs for time since first transfusion and total number of surgeries remained unchanged, while the association for anesthesia weakened. These results were generally similar for both diffuse and follicular subtypes, with the exception that total number of surgeries showed a suggestive positive association with follicular (OR=1.61 for 7+ surgeries compared to 0; 95% CI 0.74–3.51) but not diffuse NHL. Conclusion: History of blood transfusion was associated with an increased risk of NHL. Total number of surgeries, type of surgery, and use of anesthesia were only weakly associated with risk, although the suggestive positive association for number of surgeries with follicular lymphoma warrants further investigation.

Abstract Abstract 2700 Background: Follicular lymphoma is a heterogeneous disease in terms of disease course and prognosis. Clinical risk factors, including age, presence of B symptoms and bulky disease have been shown to have prognostic value. More recently, elements of the tumor microenvironment, including CD68 positive macrophages as well as programmed death-1 (PD-1) expressing lymphocytes, have been shown to be associated with a worse prognosis. However, there is a paucity of data in terms of microenvironment changes that take place in the setting of transformation into diffuse large B cell lymphoma (DLBCL). CD14 is a monocytic marker, and increased numbers of CD14+ cells in the peripheral blood have been associated with a poor prognosis in non-Hodgkin's lymphoma and CLL. It has also been shown that CD14+ cells are present in biopsy specimens in DLBCL and that these cells may support malignant cell growth. This study was designed to examine the presence of CD14+ cells in follicular lymphoma that transformed to DLBCL and to determine the prognostic value of CD14 expression in terms of time to transformation. Methods: Patients with follicular lymphoma who underwent transformation into DLBCL were identified from the Mayo Clinic Lymphoma Database. Controls were follicular lymphoma patients who did not undergo transformation, and were matched 2:1 (control:transformed) on age at diagnosis, year of diagnosis, sex, stage, and length of follow-up time. Tissue specimens at the time of diagnosis were stained for CD14 and CD68, and characterized semiquantitatively based on the presence and distribution of positive cells. Time to transformation (TTT) was assessed using the Kaplan-Meier method. Results: 159 patients were included in the study: 58 patients transformed and 101 did not transform into DLBCL. Median age at diagnosis was 64 years. 150 specimens were sufficient for immunohistochemical analysis. When patients with transformed disease were compared to those who did not transform, those who transformed had greater numbers of CD14+ cells present in their initial diagnostic biopsy (p=0.0415). When only patients who transformed were considered, CD14+ cells in a follicular pattern was associated with a median time to transformation of 3.9 years, CD14+ cells in an interfollicular pattern had a median TTT of 4.9 years and CD14- specimens were associated with a median TTT of 6.2 years (p = 0.0322). The staining pattern for CD68 differed from that of CD14 and was not significantly associated with time to transformation. Conclusions: The presence of intratumoral CD14+ cells at diagnosis in follicular lymphoma is associated with subsequent disease transformation. Our results suggest that when CD14+ cells organize in the follicle, follicular lymphoma patients are likely to transform into DLBCL sooner. Further studies are therefore warranted to define the role of these cells in the tumor microenvironment during transformation to DLBCL. Disclosures: No relevant conflicts of interest to declare.

Abstract While extensive, the genetic studies of DLBCL tumors to date have primarily focused on somatic mutations that are associated with development of lymphoma, i.e., driver mutations. Identification of key genetic events that impact and/or predict response to therapy and clinical outcome of lymphoma patients has not been accomplished. In an exploratory study, we used whole-exome sequencing to identify novel biomarkers that can predict which patients have an aggressive form of DLBCL, and therefore would likely benefit from a different and more aggressive treatment plan. Using whole-exome sequencing data from 54 newly diagnosed DLBCL patients, we evaluated the association of somatic coding single nucleotide (cSNV) and copy number (CNV) variants with aggressive DLBCL. All patients were treated with R-CHOP or immunochemotherapy, and disease aggressiveness was based on relapse, with patients classified as having aggressive disease (AD) (n=13, defined as treatment failure, relapse, or progression within 24 months of diagnosis) versus non-aggressive disease (n=41, defined as achieving at least 24 months of relapse-free survival). An in-house algorithm, patternCNV was used to detect somatic CNVs. Logistic regression was used to assess statistical significance. In the cSNV analysis, 24 genes were found to be significantly (p ≤ 0.05) associated with AD. Of these genes, CIITA (p=0.01) was previously identified as a mutational target in DLBCL and is a recurrent gene fusion partner in lymphoid cancers. Metacore analyses showed that seven of these genes, including CIITA, can be placed in the same regulatory network centered around CREB1. Interestingly, the CREB binding protein (CREBBP) is a known target of pathogenic mutations in DLBCL. In the CNV analyses, we identified 245 gene amplifications and 209 gene deletions associated with AD (p ≤ 0.05). Deleted genes were localized in three major chromosomal regions, 6p22.3-6p22.1 (26 genes), 6q13-6q16.3 (31 genes), and 6q21-6q24.2 (86 genes). In the CNV amplification analysis, the genes were localized in two major chromosomal regions, 3q12.3-3q29 (90 genes) and 19q13.12-19q13.43 (122 genes). We also quantified the association of each regional deletion/amplification with patient outcome. As expected, each deleted region was univariately associated with time to relapse: 6p22.3-6p22.1 (HR = 7.19, 95% CI: 2.66-19.46, p=1.33x10-5), 6q13-6q16.3 (HR = 4.44, 95% CI: 1.74-11.32, p=6.84x10-4), and 6q21-6q24.2 (HR = 5.42, 95% CI: 2.12-13.87, p=9.23x10-5) as well as the two amplification regions: 3q12.3-3q29 (HR = 4.60, 95% CI: 1.49-14.24, p=4.27x10-3) and 19q13.12 -19q13 (HR = 13.79, 95% CI: 4.39-43.34, p=2.81x10-8). Deletions at 6q21-6q24.2 have been previously reported in DLBCL and two tumor suppressor genes associated with lymphoma pathogenesis are localized in the region, TNFAIP3 (p=0.14) and PRDM1 (p=0.02), the latter of which was significantly associated with AD. However, the genes in the 6p21 locus that were most significant (p=0.002) were SLC22A16, GPR6, SOBP, MATTL24, DDO, and REV3L. SLC22A16, which also had cSNVs in two tumors, is an organic cation transporter that has been shown to transport chemotherapeutic drugs including doxorubicin. Successful drug response has been correlated with the level of activity and expression of this transporter in tumor cells. To determine if expression of SLC22A16 would have an impact on doxorubicin transport, and may therefore impact response to R-CHOP we overexpressed either an empty vector control or SLC22A16 in OCI-Ly7 DLBCL cells, which do not express endogenous SLC22A16 mRNA. We found that OCI-Ly7 cells expressing SLC22A16 have increased 14C-doxorubicin uptake and are more sensitive to doxorubicin-induced cell death when compared to the empty vector control cells. These data suggest that loss of SLC22A16 expression through gene deletion could impact the ability of DLBCL cells to respond to therapy and indicates an aggressive form of the disease. In summary, our data are the first to use whole exome sequencing to identify genetic variants associated with aggressive DLBCL, which will require replication in additional samples. Nevertheless, our data highlight the role for somatic CNVs in patient outcome and we biologically validate the potential impact of deletions in SLC22A16 at 6p21. Disclosures: No relevant conflicts of interest to declare.

Abstract It has been well-documented in cardiac patients and in the general population that physical activity improves physical and mental health. Physical activity could also improve the health and quality of life of long-term lymphoma survivors, but little is known about physical activity in this group of patients. Using the Mayo Tumor Registry, we identified eligible patients who were 16 years or older at diagnosis, U.S. residents, first diagnosed with Hodgkin or non-Hodgkin lymphoma from 1984–1998, diagnosed and/or initially treated at Mayo Clinic Rochester, and survived for 5 to 20 years (N=2,485). In October of 2004, we mailed a 23-page survey to 95 randomly selected patients; 7 were found to be ineligible (deceased or too ill). Of the 88 remaining patients, we were able to find a correct address for 82, and 57 completed a survey for a 70% participation rate. Physical activity was self-reported using the Godin (1985) Leisure-Time Exercise Questionnaire. Of the 54 patients with complete data for this report, the mean age at completion of the questionnaire was 60.8 years (26.1–86.7). The mean time since diagnosis was 12.0 years (6.3–19.9), and 52% survived more than 11 years. The histologies included 22 (39%) Hodgkin lymphoma, 21 (38%) diffuse large B-cell lymphoma, 3 (5%) follicular lymphomas, 1 (2%) high-grade lymphoma, 5 (9%) peripheral T-cell lymphomas, and 4 (7%) other. Regular fitness was reported by 21% of the respondents. This is lower than a recent report of adults aged 50 years and older, where approximately 40% of those free of chronic disability were attaining recommended daily physical activity levels. It is also lower than the expected 30% in patients with disabilities from the Behavioral Risk Factor Survey (Brown DR et al., Med Sci Sports Exerc2005;37:620–9). In addition, although not statistically significant, there were effect sizes observed suggesting that sedentary responders had higher levels of depression, higher anxiety levels, more distress, and lower quality of life (QOL) compared to physically active respondents. These finding need to be verified in a larger sample to obtain better estimates. In conclusion, levels of physical activity were lower than general population samples. These results also suggest that physical activity level may be related to improved mood and QOL in this population.