Link, Brian K.

Abstract Blood cytokine elevations have been associated with non-Hodgkin's lymphoma (NHL) such as follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Although other types of NHL have been studied, to our knowledge, cytokine deregulation in mantle cell lymphoma (MCL) has not been comprehensively studied. In this study, we studied cytokine levels in untreated and relapsed MCL patients using a multiplex assay to determine the role of dysregulated cytokines in these patients and study any prognostic relevance that could be drawn from their effect on relapse and survival. Samples from two data sets of MCL patients were used for this study. The first dataset was pre-treatment serum samples from newly-diagnosed patients with MCL (n=88) from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource. The second dataset included pre-treatment plasma samples from relapsed MCL patients (n=20) treated on the MC0048G clinical trial studying the effect of everolimus in lymphoma patients. In addition, unrelated controls from a case-control study of lymphoma were included (n=15 serum, n=24 plasma). Thirty cytokines were assessed using a multiplex ELISA. Differences between cytokines in cases and controls were assessed using Wilcoxon rank-sum tests; associations between cytokines and event-free survival were assessed using Kaplan-Meier curves and Cox proportional hazards models. In the newly diagnosed MCL patients, IL-10 (p<0.0001), IL-1RA (p=0.001), IL-6 (p= 0.04), sIL-2Rα (p=0.005), and MIG (p=0.002) were elevated compared to normal controls. The only significantly elevated cytokine in the recurrent MCL cases compared to controls was sIL-2Rα (p= 0.0006). High levels (above median) of sIL-2Rα levels were associated with inferior event-free-survival (EFS) in both newly diagnosed (HR=2.61 (95% CI: 1.41-4.81, p= 0.0022) and relapsed MCL (HR=2.90, 95% CI: 1.08-7.80, p=0.035) patients; this remained significant after adjusting for MIPI (p=0.01 and 0.03, respectively). Moreover, in the relapsed MCL group eotaxin (p< 0.0001), IL-12 (p< 0.0001), and MCP-1 (p= 0.0002) were suppressed compared to normal controls. We hypothesized that STAT3 (pSTAT3) in MCL cells might be the possible cause behind IL-12 suppression. Indeed, 12/13 MCL samples from IL-12-suppressed relapsed MCL patients were pSTAT3+. When studying the association between cytokine levels and clinical characteristics in both untreated and relapsed MCL groups, sIL-2R was significantly associated with the MIPI score in both untreated (p<0.0001) and relapsed (p=0.007) MCL groups; and with performance status (p=0.005), lymphoma stage (p=0.004), and B symptoms (p=0.006) in the newly diagnosed MCL group.Figure 1Event-free survival of patients with untreated and relapsed MCL by sIL-2R levels.Figure 1. Event-free survival of patients with untreated and relapsed MCL by sIL-2R levels. Our study shows that cytokines are deregulated in both untreated and relapsed MCL patients. It emphasizes on the importance of sIL-2R in its association with negative clinical parameters and worse prognosis in MCL. These findings gives the rational for using sIL-2R along with MIPI and other parameters in predicting prognosis and further to monitor response in MCL. Furthermore, we showed that IL-12 is suppressed in relapsed MCL group and that pSTAT3 expression is a possible mechanism behind this suppression. Further studies are needed to investigate the effect of drugs that suppress pSTAT3 expression in IL-12 suppressed MCLs and disease progression in relapsed MCL patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Follicular lymphoma (FL) is an indolent lymphoma generally considered incurable with current standard therapies. Recent advances have resulted in prolongation of overall survival (OS) for patients with FL such that death from competing causes may now limit the mortality impact of FL in some patient groups. Identification of patients for whom FL related mortality is expected to be minimal, or conversely those at high risk of disease related mortality, is highly clinically relevant. We recently reported (Maurer et al, JCO 2014;32:1066-73) that event-free survival (EFS) at 24 months from diagnosis is a robust endpoint for disease related outcome in patients with diffuse large B cell lymphoma (DLBCL). Here we use the same approach to assess if landmark timepoints of EFS can stratify subsequent OS in FL. Methods: All newly diagnosed grade 1-3a FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2011 were eligible. Patients with grade 3b FL, transformation, or presence of DLBCL at diagnosis were excluded. EFS was defined as time from diagnosis to progression, relapse, re-treatment, or death due to any cause. EFS12 was defined based on EFS status 12 months after date of diagnosis; we also assessed EFS at 24 months. OS was defined as time from a specific timepoint (diagnosis, event, or EFS12) until death due to any cause. OS was compared to age and sex matched survival in the general US population using an expected survival approach and standardized mortality ratios (SMR) and 95% confidence intervals (CI). Outcomes were examined in all patients as well as selected subsets defined by initial treatment. Replication was performed using a Lyon, France hospital registry of newly diagnosed grade 1-3a FL patients enrolled from 2002-2010 with survival compared to French population data. Results: 936 patients with grade 1-3a FL were eligible from the MER. The median age at diagnosis was 60 years (range 19-91) and 53% were male. 86% had grade 1-2 disease and 14% grade 3a disease. 23% had high-risk disease (FLIPI score ≥3). 347 (37%) were initially treated with alkylator or anthracyline based immunochemotherapy (IC), 113 (12%) rituximab monotherapy (RM), and 318 (34%) were initially observed; the remaining patients received radiation for limited stage disease (8%), chemotherapy without rituximab (4%), or other therapy (5%). At a median follow-up of 59 months (range 1-131), 403 patients (43%) had an event and 120 patients (13%) had died; 155 patients (17%) failed to achieve EFS12. From diagnosis, patients with FL had inferior OS compared to the general population (SMR=1.24, 95% CI: 1.03-1.48, p=0.018); results were similar for patients with grade 1-2 (SMR=1.23) and grade 3a (SMR=1.29) disease. The survival deficit was eliminated in patients who achieved EFS12 (SMR=0.85, 95% CI: 0.66-1.09, p=0.20, Fig 1a), and so we did not pursue modeling EFS24. In contrast, patients with a non-death event (relapse, retreatment, or progression) within 12 months of diagnosis had inferior subsequent OS (SMR=3.90, 95% CI: 2.89-5.25, p=4.8x10-19, Fig 1b). These results were replicated in 153 FL patients from the Lyon registry: patients who achieved EFS12 had equivalent subsequent OS to the general French population (SMR=0.82, 95% CI: 0.39-1.72, p=0.60, Fig 1c), while patients who failed to achieve EFS12 had poor subsequent OS (SMR=4.16, 95% CI: 1.34-12.91, p=0.013, Fig 1d). In subset analysis of the MER, patients achieving EFS12 initially treated with IC (SMR=0.98, 95% CI: 0.63-1.54, p=0.93), RM (SMR=0.66, 95% CI: 0.31-1.38, p=0.27), or observation (SMR=0.73, 95% CI: 0.47-1.15, p=0.18) had equivalent OS to the population. In contrast, for patients not achieving EFS12, OS after event was inferior for those treated with IC (SMR=15.0, 95% CI: 10.22-22.05, p=2.0x10-43) or RM (SMR=4.96, 95% CI: 1.24-19.84, p=0.023), while trending towards inferior for those initially observed (SMR=1.55, 95% CI: 0.81-2.99, p=0.19). Summary: Events within the first 12 months of diagnosis are associated with poor OS in FL, especially in patients treated with IC, while patients achieving EFS12 have excellent subsequent survival, overall and in the main treatment subsets. Prognosis for FL patients should be recalibrated at 12 months from diagnosis. EFS12 will be useful in counseling and should be considered as an endpoint in studies of newly diagnosed FL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Purpose: The purpose of this study was to examine whether quality of life (QOL) scores at diagnosis predict survival among patients with aggressive lymphoma, controlling for clinical variables and histological subtype. Patients and Methods: Newly diagnosed lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource. Eligibility criteria included age ≥18 years; exclusion criteria included HIV-positive, non-US residency, and inability to participate in an interview conducted in the English language. All pathology was reviewed by a lymphoma hematopathologist. For purposes of this analysis, we considered “aggressive lymphoma” to include the histological subtypes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) grade III, mantle cell lymphoma, T-cell lymphoma excluding mycosis fungoides and cutaneous types, and other (Burkitt lymphoma, high grade B-cell lymphoma NOS, grey zone, etc). Baseline QOL was measured at time of registry enrollment with the Functional Assessment of Cancer Treatment-General scale (FACT-G), which measures 4 QOL domains: physical, social/family, emotional, and functional well-being (WB); a single item Linear Analogue Self Assessment (LASA) for measuring overall QOL; and a LASA measuring spiritual WB. Patients who did not complete ≥80% of FACT-G QOL questions were excluded. Clinical data were abstracted and patients were systematically followed for event-free and overall survival (EFS, OS). QOL scores were transformed to a 0-100 scale for modeling. Generalized additive models were used to account for timing of QOL assessment in relation to treatment and diagnosis; residuals from these models were then used to assess association between QOL measures and outcome via univariate and multivariable (adjusted for IPI and subtype) Cox proportional hazards models. Results: From September 2002 to December 2009, 701 patients with aggressive lymphoma who completed baseline QOL questionnaires were enrolled and eligible for this analysis. ; Subtype was 60% DLBCL, 14% mantle cell, 11% FL grade III, 13% T-cell, and 1% other subtypes. The median age was 62 years (range 18-92), and 58% were male. At a median follow-up of 71 months (range 6-128), 316 patients (45%) had an event and 228 patients (33%) died. Patient-reported QOL was prior to therapy in 330 patients (47%) and after initiation of therapy in 371 (53%). The median overall FACT-G total score was 83 (IQR 70-93), and the median scores on the functional WB, physical WB, emotional WB, and social/family WB were 18 (13-23), 22 (17-26), 18 (16-21), and 25 (22-27), respectively. 42 patients (6%) reported a clinically deficient QOL score on the FACT-G (score ≤50 on 0-100 scale). When comparing QOL scores between those who were on active therapy versus those who were not yet treated, physical WB (p<0.0001) functional WB (p=0.00014), and total FACT-G (p=0.0013) were lower in those on active treatment. All QOL measures but emotional WB were significantly associated with OS (all p<0.04), and all but LASA spiritual WB remained significant after adjusting for IPI and NHL subtype. Associations were stronger for OS than EFS. For OS, the strongest associations were with total FACT-G (adjusted HR=0.86, 95% CI: 0.79-0.94, p=0.00062) and functional WB (adjusted HR=0.88, 95% CI: 0.83-0.93, p<0.0001). The one-question QOL LASA was also associated with OS (adjusted HR=0.92, 95% CI: 0.87-0.97, p=0.0041). The strongest association with EFS was with functional WB (adjusted HR=0.92, 95% CI: 0.88-0.97, p=0.0015). Patients with a clinically deficient QOL (baseline overall QOL ≤50) had a median OS of 59 months compared to 121 months for patients with baseline QOL >50, p=0.0002, figure 1. In a sensitivity analysis, raw QOL was modeled for OS and EFS in the subset of patients with QOL assessed prior to treatment; hazard ratios were consistent with the adjusted QOL HR in all patients. Conclusions: In this large sample of patients with aggressive lymphoma, baseline QOL is predictive of OS and EFS, even after adjustment for known factors related to survival (IPI and histological subtype). This provides evidence that patient-reported outcomes are as important as other more objective previously confirmed IPI measures. QOL should be assessed at diagnosis as a prognostic factor in patients with aggressive lymphoma. Figure 1 Association of QOL with overall survival. Figure 1. Association of QOL with overall survival. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 3708 Background: There are few prospective studies on disease characteristics, patterns of care, response, and outcomes in elderly FL patients (pts) in the US. The NLCS is a Genentech-sponsored prospective multicenter registry study that collects this information without study-specific treatment. We utilized the NLCS database to better understand the impact of age on FL outcome. Patients and Methods: All evaluable pts with FL histology in the NLCS were included except pts with FL plus other lymphoma histology or pts who progressed before first treatment or before being assigned to watchful waiting (WW). Using Pearson Chi-Square tests, associations of age groups (≤60, 61–70, >70) with disease characteristics and overall response (ORR) were examined. Median PFS and OS by treatment regimen were estimated using Kaplan-Meier methods for each age group. Cox proportional hazards regression adjusted for baseline factors (grade, number of nodal sites, LDH, Hgb, stage, performance status (PS), bone marrow (BM) involvement, race, and treatment center type) were used to assess treatment differences in PFS and OS and the significance of age by treatment interactions. Results: Of 2,647 pts, 47% (n=1,254) were ≤60 yrs, 25% (n=666) were 61–70 yrs, and 27% (n=727) were >70 yrs (min age of 22; max of 97). Compared with pts ≤60 yrs, pts 61–70 and >70 were more likely to be white (93% >70, 92% 61–70, and 88% ≤60, P=.02 and .02 respectively), have stage I/II disease (37% >70, 36% 61–70, and 29% ≤60, P=.0008 and .0003), have <5 nodal sites (73% >70, 69% 61–70, and 61% ≤60, P=.001 and <.0001), and have poor-risk FLIPI (53% >70, 51% 61–70, and 15% ≤60, P<.0001 and <.0001). Compared with pts ≤60, elderly pts (>70) were more likely to have FL grade 3 (24% vs 18%, P=.01). While there were no differences in geographic distribution by age, elderly pts were more likely to receive therapy at community practices (86%) versus academic institutions than pts ≤60 (77%, P<.0001) or 61–70 (81%, P=.004). Treatments varied significantly by age (P<.0001). More elderly pts were observed compared to pts ≤60 (23% vs19%). When treated, elderly pts (22%) were more likely to receive rituximab (R) monotherapy compared with patients aged 61–70 (12%) or ≤60 (10%). When chemotherapy alone or plus R was given, elderly pts were less likely to receive anthracyclines (45% vs 65% (61–70) and 68% (≤60)). Among all variables, only grade 3 histology predicted anthracycline use in all age groups. Lack of BM involvement predicted anthracycline use for younger pts (≤60 and 61–70). Of those ≤60, white pts were more likely to receive anthracyclines, and of those 61–70, those with ≥5 nodal sites were more likely to receive anthracyclines. ORRs were similar across age groups receiving similar regimens with R plus chemo providing the highest ORR. Adjusting for baseline factors, treatment (WW, R, R-Chemo, or other) benefit varied for each age group in terms of PFS (P=.02), with treatment outcomes being most differentiated among younger pts (Table). PFS appeared shorter in elderly pts regardless of the treatment received. No significant interaction between age and efficacy of anthracycline in terms of PFS or OS was observed (P-values >.65), but the overall effect of anthracycline for all pts was beneficial for PFS (HR=0.80, P=.02) and OS (HR=0.67, P=.003). Median OS was 8 years for elderly and not reached for others. After adjusting for baseline factors, no significant differences in treatment impact by age on OS were seen. Elevated LDH, reduced Hgb, stage III/IV, PS ≥1, and BM involvement were all significantly associated with shortened OS. These factors were also significantly associated with treatment choice, as worse-prognosis elderly pts were more likely to receive either R or R+chemo than WW or other treatment. Conclusions: FL pts >70 yrs more commonly received R alone and less commonly received anthracyclines when treated with chemotherapy. The impact of anthracyclines on PFS did not vary by age, but differences in PFS for other treatment regimens showed a stronger association among younger pts Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau. Byrtek:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Dawson:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Link:Genentech, Inc., a member of the Riche Group: Consultancy; Celgene: Consultancy; Spectrum: Consultancy. Friedberg:Genentech: Consultancy. Cerhan:Genentech: National LymphoCare Scientific Advisory Board Other. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy, Research Funding; Genentech: Consultancy; GIlead: Research Funding; Spectrum: Research Funding; Janssen: Research Funding; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 684 Background. Obesity has been associated with an increased risk of developing of lymphoma, particularly DLBCL. Genetic variation in several energy balance genes, including leptin (LEP), its receptor LEPR, ghrelin (GHRL) and neuropeptide Y (NPY) have been shown to modulate risk of lymphoma, although their impact on survival is not known. In contrast, recent studies suggest that patients either overweight (Body Mass Index (BMI), 25 to<30 kg/m2) or obese (≥30 kg/m2) may have a superior prognosis in DLBCL, although its impact in FL and in the current treatment era is not known. We evaluated the association of BMI at the time of diagnosis, 2 years prior to diagnosis and at ages 18, 35 and 50 years, along with germline genetic variation in selected energy balance genes with event-free (EFS) and overall (OS) survival in DLBCL and FL. Methods. We evaluated these associations in a prospective cohort of newly diagnosed DLBCL (N=764) and FL (N=649) patients enrolled at the Mayo Clinic and University of Iowa from 2002–2009 as part of the Molecular Epidemiology Resource. Peripheral blood DNA, clinical data and self-reported historical weights were collected at enrollment. Patients received standard disease treatment strategies, and were systematically followed for disease progression, re-treatment, and death. Single nucleotide polymorphisms (SNPs) were genotyped as part of a custom Illumina iSelect panel. The most prevalent homozygous genotype was used as the reference group, and each SNP was modeled as having a log-additive effect in the regression model. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of the obesity measures and SNPs with outcome, adjusted for treatment class and subtype specific prognostic factors (IPI, FLIPI). Results. For DLBCL patients (median age 63 years, range 18–92) the median follow-up was 47 months (range 0–101); 58% had an IPI 0–1 risk disease; and 87% received immunochemotherapy. For FL patients (median age 60 years, range 25–94), the median follow-up was 60 months (range 11–110); 24% had FLIPI score 3–5; and main initial treatments were observation (32%), rituximab (R)-monotherapy (12%), CVP +/−R (19%), and anthracycline +/−R (22%). The main results for BMI and prognosis are reported in the Table. For DLBCL, obese patients at diagnosis had better EFS and OS; this association was weaker for BMI at age 50 and 35 years. In contrast, for FL, overweight and obese patients at diagnosis had a poorer EFS and OS, and this was also observed for BMIs two years before diagnosis and at ages 50 and 35 years. In FL, the LEP SNP rs2167270 was associated with inferior EFS (HR=1.25; 95%CI 1.05–1.49) and OS (HR=1.28; 95%CI 0.90–1.83). The NPYSNP rs16147 was associated with inferior FL OS (HR=1.50; 95%CI 1.03–2.17) but was not associated with EFS. None of the energy balance and metabolism SNPs were associated with DLBCL EFS or OS. Conclusions. Higher BMI prior to and at diagnosis, as well as SNPs in LEP and NPY,were significantly associated with FL prognosis, with inferior outcomes in overweight and obese patients. These novel findings in the modern treatment era suggest an important role of obesity pathways in FL prognosis. In DLBCL, we confirm the recent findings of improved survival in DLBCL in obese patients, and extend this to the modern treatment era and BMI earlier in life. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3637 Background: A recent large genome-wide association study confirmed the important role of the major histocompatibility complex in classical Hodgkin Lymphoma (cHL) susceptibility (rs6903608), but also identified significant associations with genetic variants outside of the HLA region at chromosomal regions 2p16.1 (REL, rs1432295), 8q24.21 (PVT1, rs2608053, rs2019960), and 10p14 (GATA3, rs501764, rs485411). These single nucleotide polymorphisms (SNPs) are localized in or near important genes involved in lymphoma pathogenesis: REL, which encodes for c-rel, is a member of NFkB pathway; PVT1, which is downstream of the MYC locus, encodes for non-coding microRNAs, some of which have oncogenic properties; and GATA3, which is a critical transcriptional factor for priming lymphoid T-cells for Th2 phenotype, is aberrantly expressed in HL. We investigated whether these six SNPs described in cHL etiology also influence the outcome of newly diagnosed cHL patients in two independent cohorts. Patients and Methods: The first cohort consisted of 342 cHL patients from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) who were prospectively enrolled between 1998 and 2002. The second cohort consisted of 259 patients prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER). DNA for genotyping was extracted from a blood samples collected at diagnosis, and genotyping was conducted using Taqman technology (ABI Prism 7000, Applied Biosystems) for HLA-DRA, PVT1, GATA3 and PCR-based restriction fragment length polymorphism for REL in GELA cohort and Illumina iSelect for the 6 SNPs in MER cohort. Both cohorts were followed for disease progression, re-treatment and death. In the GELA series, the median age was 32 years (range, 15–93), 57% were male, and 72% had an Ann Arbor stage I–II. Histology was nodular sclerosis in 84%, and 29% of available cases (n=40/140) were EBV positive. In the MER series, the median age was 38 years (range, 18–89), 53% were male, and 53% had an Ann Arbor stage I-II. Nodular sclerosis was the most common subtype (62%) and 23 of 115 available cases were EBV positive (20%). The International Prognostic Score (IPS) was 0–1 in 46% and 52% of GELA and MER patients, respectively. ABVD regimen was used for 60% and 88% of the GELA and MER patients, respectively. The 5-year progression free survival (PFS) was 83% and 75% in GELA and MER cohorts, respectively. We estimated the prognostic value of each individual SNP for PFS for allelic and genotypic (dominant and recessive) modes of transmission in each series. In order to increase power, we then performed a meta-analysis of the two studies. Results: Consistent with prior reports, the minor allele frequencies for REL (rs1432295), HLA-DRA (rs6903608), PVT1 (rs2608053), PVT1 (rs2019960), GATA3 (rs501764) and GATA3 (rs485411) were 0.44, 0.50, 0.43, 0.29, 0.22, 0.28 in the GELA and 0.46, 0.41, 0.46, 0.27, 0.25, 0.31 in the MER series, respectively. In GELA, GATA3 (rs501767) was associated with PFS in the ordinal model (HR=1.66, 95%CI 1.11–2.49, P=.01), while there were suggestive associations for PVT1 (rs2608053) (HR=1.76, 95%CI 0.95–3.26, P=.07) and REL (rs1432295) (HR=0.63, 95%CI 0.37–1.06, P=.08) in the dominant model. In the MER, PVT1 (rs2608053) was associated with PFS in the ordinal model (HR=1.42, 95%CI 0.99–2.03, P=.06), while there was a suggestive association with HLA-DRA (rs6903608) in the dominant model (HR=0.64, 95%CI 0.39–1.05, P=.08) for whole cohort but also for EBV negative cHL (HR=0.41, 95%CI 0.17–0.99, P=.05). In a meta-analysis of the two studies, PVT1 (rs2608053) was significantly associated with PFS in the ordinal (HR=1.34, 95%CI 1.04–1.73, P=.02) and the dominant (HR=1.88, 95%CI 1.20–2.95, P=.006) models. Further adjustment for IPS had minimal impact on these associations (ordinal HR=1.30, 95%CI 1.00–1.70; dominant HR=1.78, 95%CI 1.13–2.83). Patients with PVT1(rs2608053) GG, GA, AA genotypes had a 5-year PFS rate of 83%, 74% and 73% in GELA and 86%, 70%, and 73% in the MER, respectively. Conclusions: The non-HLA cHL susceptibility locus PVT1 (rs2608053) was associated with PFS in two independent cohorts of cHL cases, and after adjustment for the IPS. While associations with GATA3 and REL were only observed in one of the studies, their evaluation in other studies is warranted. Functional studies of PVT1 in cHL pathogenesis should be pursued. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3702 Background: Both drug choice and delivered dose of intended treatment potentially influence outcome in patients treated for follicular lymphoma (FL). Historically, observational studies have solely evaluated drug choice. The National LymphoCare Study (NLCS) is a prospective, observational study that enrolled >2700 patients with FL in the United States between 2004 and 2007. We report on measures of delivered dose and its impact on outcomes for the most common first-line regimens. Methods: All evaluable patients treated with R-CHOP, R-CVP, or R-fludarabine (R-Flu)–containing regimens in the NLCS were included, except those with FL plus other lymphoma histology, non-FL histology, or those who progressed before first treatment or before being assigned to watchful waiting. Associations between baseline factors and choice of treatment (R-CHOP, R-CVP, or R- Flu–containing regimen), number of cycles received (≤4, 5–6, 7+), and completion of therapy were assessed using the Pearson chi-square test. Factors associated with risk of early discontinuation were assessed using logistic regression, and a generalized logits model was used to assess the relationship between baseline factors and number of cycles received. Kaplan-Meier methods and the log-rank test were used to estimate progression-free survival (PFS), overall survival (OS), and time to next treatment. Results: Among 1165 evaluable patients, a total of 648 received R-CHOP, 296 received R-CVP, and 221 received R-Flu combinations. Patient characteristics were similar between groups with the following exceptions: patients receiving R-CHOP were more likely to have grade 3 FL (38% vs 11% for R-CVP and 13% for R-Flu), and patients receiving R-CVP were older (25% ≥75 vs 8% for R-CHOP and 13% for R-Flu) and had higher Follicular Lymphoma International Prognostic Index (FLIPI) risk scores (50% poor FLIPI vs 41% for R-CHOP and 36% for R-Flu). The distribution of delivered cycles demonstrated a high degree of compliance with published regimens, with most patients receiving ≥5 cycles of treatment (R-CHOP 86%, R-CVP 81%, R- Flu 67%, P<.0001). The median cycle length was 21 days for both R-CHOP and R-CVP, and 29 days for the R-Flu regimens. Cycle intensity, defined as the expected cycle length (21 days for R-CHOP and R-CVP, and 28 days for R-Flu) divided by the actual cycle length, was between 0.9 and 1.1 for 68% of R-CHOP patients, 75% of R-CVP patients, and 45% of R-Flu patients. The percentage of patients with longer-than-expected time between cycles (cycle intensity <0.9) was similar for the 3 treatment groups; however, R-Flu patients were more likely to have shorter-than-expected time between cycles (24% vs 4% for R-CHOP and 3% for R-CVP). We sought to understand the reasons for patients receiving ≤4 cycles. Most patients who received ≤4 cycles were considered to have completed the intended duration of therapy (58% for R-CHOP, 62% R-CVP, and 75% R-Flu); rates of early discontinuation from the intended treatment were significantly less for patients receiving ≥5 cycles. Early discontinuation was associated with age ≥75 years and treatment with R-Flu (particularly in patients with grade 1–2 FL). Toxicity was the most commonly cited reason for early discontinuation (47% for R-CHOP, 46% for R-CVP, and 71% for R-Flu). The higher rate of R-Flu discontinuation due to toxicity is consistent with findings from other studies. Disease progression was rarely cited as the reason for early discontinuation. Time to retreatment was significantly shorter for patients receiving ≤4 cycles for patients receiving R-CHOP and R-CVP compared with patients receiving 5–6 cycles and 7+ cycles (P=.002 and P<.001 respectively; medians not yet reached). Delivery of ≤4 treatment cycles was associated with lower response rates (76% CR/PR vs 90% for 5–6 cycles and 92% for 7+ cycles) and worse PFS and OS, among patients who received R-CVP (all P<.01) but not among other regimens. Conclusions: Most patients with FL receiving chemoimmunotherapy in the NLCS completed ≥5 cycles of treatment. Most who received fewer cycles were considered to have completed therapy, and therapy commonly was given at or above the expected cycle intensity. Strategies to improve dose delivery appear unlikely to impact patient outcomes, except possibly in patients receiving R-CVP. Disclosures: Martin: Genentech: Speakers Bureau. Link:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrtek:Genentech: Employment. Dawson:Genentech, A Member of the Roche Group: Employment. Friedberg:Genentech: Membership on an entity's Board of Directors or advisory committees. Cerhan:Genentech: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech: Membership on an entity's Board of Directors or advisory committees.

AbstractBackgroundHuman pegivirus (HPgV) is a single-strand RNA virus belonging to the Flaviviridae. Although no definitive association between HPgV infection and disease has been identified, previous studies have suggested an association of HPgV viremia with risk of lymphomas.MethodsWe conducted a systematic review and meta-analysis, including 1 cohort study and 14 case-control studies, assessing the association of HPgV viremia with adult lymphomas. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model, overall and by geographic region and lymphoma subtype.ResultsThe overall OR for lymphoma was 2.85 (95% CI, 1.98–4.11), with statistically significantly elevated ORs observed in 8 of 15 studies. There was a small amount of heterogeneity among studies (I2 = 28.9%; Q = 18.27, P = .16), and the funnel plot provided no evidence for publication bias. The strongest association with lymphoma risk was observed for studies from Southern Europe (OR, 5.68 [95% CI, 1.98–16.3]), whereas weaker ORs (with 95% CIs) were observed for studies from North America (2.24 [1.76–2.85]), Northern Europe (2.90 [.45–18.7), and the Middle East (2.51 [.87–7.27]), but all of similar magnitude. Participants with HPgV viremia had statistically significantly increased risks (OR [95% CI]) for developing diffuse large B-cell (3.29 [1.63–6.62]), follicular (3.01 [1.95–4.63]), marginal zone (1.90 [1.13–3.18]), and T-cell (2.11 [1.17–3.89]) lymphomas, while the risk for Hodgkin lymphoma (3.53 [.48–25.9]) and chronic lymphocytic leukemia (1.45 [.45–4.66]) were increased but did not achieve statistical significance.ConclusionsThis meta-analysis supports a positive association of HPgV viremia with lymphoma risk, overall and for the major lymphoma subtypes.

AbstractEpidemiologic studies show an increased risk of non‐Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen‐stimulation in one disease leads to another. Here we assess shared genetic risk in genome‐wide‐association‐studies (GWAS).Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B‐cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta‐analysis.Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta‐analysis (combing AD with NHL) implicated genes of apoptosis and telomere length.This GWAS‐based analysis four NHL subtypes and three ADs revealed few weakly‐associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Abstract In this month's CME article, an analysis of over 1300 patients with diffuse large B-cell lymphoma (DLBCL), Wang et al demonstrate that the approximately 13% of patients with concurrent indolent lymphoma at diagnosis had the same prognosis as those patients with isolated DLBCL.