Citations

Abstract Abstract 1563 Intro: Optimal treatment for non-follicular low grade B-cell lymphoma (NFLGL) is not well defined. Clinical trial design for these subtypes would be enhanced by further understanding of early presentation and management. A large prospective observational study was used to identify presenting clinical features, describe patterns of care and compare the prognostic utility of International Prognostic Index (IPI) and the Follicular Lymphoma International Prognostic Index (FLIPI). 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. 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. This analysis includes 198 patients diagnosed with extranodal marginal zone (EMZL), 22 with nodal marginal zone (NMZL), 47 with splenic marginal zone (SMZL), 48 with lymphoplasmacytic lymphoma (LPL), as well as 67 patients with unclassifiable low-grade B-cell lymphoma (B-NOS). Results: 382 newly diagnosed NFLGBL patients were enrolled in the MER from 2002–2009. The median age at enrollment was 63 years (range 22–95). 52% were male. The most common types of initial therapy after diagnosis were observation (41 %), alkylator- based chemotherapy +/− rituximab (R) (17%), radiation therapy alone (15%) and R monotherapy (13%). At median follow-up of 60 months (range 1–121), 51 patients were deceased and 155 had an event. The clinical characteristics that comprise the IPI and FLIPI were similar across the subtypes. Approximately half of the cases presented at low risk (55% IPI; 48% FLIPI). A majority had a normal LDH (81%), limited nodal involvement (91% had ≤ 4 groups), normal hemoglobin (71% ≥12 g/dL), good performance status (95% 0–1), and advanced stage (57% stages III-IV). There were notable differences among the NFLGBL subtypes. Patients with SMZL and LPL presented with high risk FLIPI of 3–5 (49% and 46% respectively) and high to high-intermediate IPI of 3–5 (21% and 13%). Abnormal LDH and anemia (< 12 g/dL) were more frequent in patients with SMZL (40%; 56%) and LPL (25%; 62%). EMZL presented with lower stages (70% stage I-II) and NMZL presented with increased nodal involvement (38% >4 sites). SMZL had the highest rates of surgical resection (21%) and EMZL was more frequently treated with radiation therapy (25%). LPL (30%) and NMZL (32%) more commonly received alkylator based chemotherapy +/− R. While both IPI and FLIPI differentiated outcome in these patients, FLIPI had higher c-statistics than IPI for both EFS (0.583 vs 0.568) and OS (0.685 vs 0.661), respectively. Conclusions: This large prospective collection of data on NFLGBL patients presenting to academic medical centers provides a modern picture of presentation and management patterns useful to investigators designing clinical trials. FLIPI may have more prognostic utility than IPI in this group of patients. Disclosures: Ansell: Seattle Genetics, Inc.: Research Funding.

Abstract Abstract 1573 Background. Treatment of non-Hodgkin lymphoma (NHL) can lead to the development of cardiovascular disease (CVD). In a previous report, we found that the risk of CVD in patients with NHL diagnosed in the recent treatment era (since 2002) was approximately 1% per year after the initial diagnosis of lymphoma. We evaluated the association of 30 candidate single nucleotide polymorphisms (SNPs) in genes associated with anthracycline-induced cardiotoxicity in children (SLC10A2, SLC28A3, ABCC1, ABCB3, CBR3, FMO2, SPG7) and genes associated with venous thromboembolism (VTE) in adults (ABO, F2/CKPA5, F5, F11, KLKB1, SCUBE1, SLC19A, SELP) with the risk of new onset cardiovascular disease in a cohort of NHL patients. Methods. All patients were from the Mayo component of the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, and were enrolled from 2002–2008. The MER offers enrollment to all consecutive patients with newly diagnosed NHL who are US residents and age >18 years. Clinical data from the time of diagnosis and treatment data are abstracted from medical records using a standard protocol. Patients are prospectively contacted via telephone or in person per protocol every 6 months for the first 3 years from diagnosis and yearly afterwards to assess disease status and development of comorbid conditions. CVD events, including heart failure (HF), myocardial infarction (MI), arrhythmia, pericarditis, and valvular heart disease, occurring after diagnosis were identified during follow-up and validated against medical records. HF was validated with the Cardiovascular Health Study Criteria and/or the Framingham Criteria. MI was validated using case definition standards of coronary heart disease, while arrhythmia, pericarditis, and valvular heart disease were validated using clinical definitions. Genotyping was conducted using a custom Illumina iSelect platform. Cox regression was used to estimate Hazard Ratios (HRs) and 95% confidence intervals (CI) for individual SNPs with time to CVD, with death modeled as a competing risk. Each SNP was modeled with the most prevalent homozygous genotype used as the reference group, and each SNP was modeled as having a log-additive (per minor allele) effect in the regression model. An ordinal test was used to assess the trend, and p<0.05 was considered statistically significant. Results. There were 805 newly diagnosed NHL patients with no history of CVD at time of lymphoma diagnosis and had genotype data available for analysis. The median age at diagnosis was 61 years (range, 21–93) and 53% were male. The most common subtypes were follicular lymphoma (33%), diffuse large B-cell lymphoma (29%), and marginal zone lymphoma (14%). Anthracycline-based chemotherapy as initial therapy or at re-treatment was used in 51% of the patients and radiation therapy was used in 18%. Median follow-up of all cases was 59 months (range, 1–105). There were 36 incident CVD events (4.5%) and 139 deaths (17%). The most common CVD events were arrhythmia (N=17) and heart failure (N=14). There was no association with any of the anthracycline-induced cardiotoxicity genes and risk of CVD overall or in the subgroup of patients (N=406) who received an anthracycline. Of the venous thromboembolism (VTE) SNPs, rs4253399 in F11 (coagulation factor 11) with a minor allele frequency of 0.39 was associated with risk of CVD (HR=2.14; 95%CI 1.35–3.40; p=0.001). When restricted to anthracycline-treated patients, the HR for rs4253399 became stronger (HR=2.56; 95%CI 1.39–4.72; p=0.003), and an ABOSNP (rs660340) with a minor allele frequency of 0.43 became significant (HR=2.14; 95%CI 1.13–4.04; p=0.02). Conclusions. This is the first report that genes involved in VTE also predict CVD risk in NHL patients, particularly those treated with anthracycline chemotherapy. However, SNPs from genes previously associated with anthracycline-induced cardiotoxicity were not associated with CVD risk in this cohort, although those SNPs were identified in children and may not apply to adults. Future research will need to validate these findings and identify additional genetic markers that can be incorporated into risk assessment for CVD in this patient population. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2893 Introduction: Monoclonal B-Cell Lymphocytosis (MBL) is a common asymptomatic condition characterized by a clonal B-cell population detected in the blood or bone marrow. The prevalence of MBL is approximately 3–5% in adults over age 40 but rises with age. MBL is a precursor state to CLL and other types of indolent non-Hodgkin lymphoma (NHL). Only a small subset of patients with MBL comes to clinical attention, typically during evaluation for low grade lymphocytosis (designated now as clinical MBL). The rate of progression to CLL requiring treatment among individuals with clinical MBL is ∼1%/yr, and the vast majority of patients with MBL will never develop a B-cell malignancy. Recent data indicate that individuals with MBL are at increased risk of infection similar to CLL. It is unknown whether individuals with MBL are at risk for other adverse outcomes associated with CLL, such as increased risk of non-hematologic cancers (NHC). We investigated the incidence of NHC among patients with clinical MBL and compared this to a cohort of general medicine patients and a cohort of CLL patients. Methods: Mayo Clinic Rochester (MCR) is the primary center for hematologic care in a region including southeastern Minnesota, northern Iowa, and western Wisconsin. No other hematology specialty centers are available within a 50 mile radius of MCR. To explore the risk of NHC in a local, community dwelling cohort of individuals with clinically-identified, CLL-phenotype MBL, we used the MCR CLL database to identify all individuals with newly diagnosed MBL seen in the MCR Hematology Division between January 1, 1999 and December 31, 2009. Analysis was limited to 154 MBL cases residing within 50 miles of MCR. The comparison cohort consisted of 596 adult general medicine patients, with no prior cancer, residing within 50 miles of MCR, who were seen for a general medical exam and enrolled as controls in a case-control study for NHL between April 25, 2004 and December 31, 2009. Rates of NHC in the MBL cohort were also compared to a cohort of 174 patients with newly diagnosed CLL seen in the same time interval as the MBL cohort and also living within 50 miles of MCR. NHC were identified using the Mayo Clinic Cancer Tumor Registry as well as review of medical records in all 3 cohorts. Patients with a NHC diagnosis >3 months prior to the diagnosis date of MBL/CLL were excluded from analysis while those with MBL/CLL and a NHC within 3 months of one another were considered to have a concurrent diagnosis. Results: There were 125 patients in the MBL cohort, 153 in the CLL cohort, and 596 in the control cohort after excluding patients with prior cancers. The MBL and CLL patients tended to be older (median age MBL=69, CLL=68, Control=58; p<0.0001) and more likely to be male (% male MBL=61, CLL=67, Control=46; p<0.0001) than the controls. After a median follow-up of 4.2 years (range 0–11), 20 (16%) individuals with MBL developed NHC as compared to 22 (4%) of the controls (Hazard Ratio (HR) MBL relative to control=5.0; 95% confidence interval (CI)=(2.6, 9.4; p<0.0001). Twenty CLL patients (13%) developed NHC, supporting a similar rate to that of MBL patients (HR MBL relative to CLL=1.3; 95% CI=(0.6, 2.5; p=0.49;See Figure). Specifically, the MBL cohort had a higher incidence of cancer of the breast, lung, and nervous system than that of the control cohort. The higher risk of NHC among individuals with CLL and MBL persisted even when patients with “concurrent diagnosis” of CLL/MBL and NHC were excluded (p=0.006) and when patients treated for progressive CLL were censored at the date of treatment (p=0.001) Finally, we performed a pooled multivariable analysis of all patients (n=874) adjusting for age, sex, major co-morbidities, presence of MBL, and diagnosis of CLL. Age (HR each year older=1.03; 95% CI 1.01–1.06; p=0.003), major comorbidities (HR=1.81; 95% CI 1.07–3.00; p=0.02), CLL (HR=2.10; 95% CI 1.01–4.01; p=0.04), and MBL (2.47; 95% CI 1.30–4.69; p=0.02) were independent risk factors for NHC. The results were similar when the effects of age was modeled in a non-linear (e.g. logarithmic) manner. Conclusions: In this cohort study, patients with newly diagnosed clinical MBL had a 2.5-fold increased risk of developing NHC relative to the control cohort. MBL was an independent risk factor for development of NHC after adjusting for age, sex, and other comorbidities. This finding adds to the growing evidence that clinical MBL has a distinct clinical phenotype. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.

Abstract BACKGROUND: Diffuse large B-cell lymphoma, not otherwise specified (DLBCL), though defined as one disease entity, consists of two main cell-of-origin (COO) subtypes, germinal center B-cell like (GCB) and activated B-cell like (ABC), with the latter predicting a significantly worse prognosis using conventional chemotherapy. Up to 40% of all patients diagnosed with DLBCL will experience relapse, and outcomes are generally poor in this setting. In this study, we examine the proportion of GCB vs. non-GCB subtypes at initial diagnosis and at time of relapse, and assess the incidence of reclassification from one subtype to another. 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. All relapse events were validated by review of the medical record. This analysis includes patients diagnosed with DLBCL who underwent initial treatment and subsequently experienced relapse as confirmed by biopsy. Immunohistochemical staining data including CD10, Bcl-6, and Mum-1, were collected from available pathology reports and classified to either GCB or non-GCB subtypes as predicted by the Hans algorithm. We compared subtype classification and individual immunohistochemical data both at the time of diagnosis and relapse. The overall subtype agreement between the two diagnostic time points was assessed. RESULTS: 1023 patients with newly diagnosed DLBCL were enrolled in the MER from 2002 - 2012. Of those, 249 had documented disease relapse. Of those analyzed, a total of 43 patients had COO classification based on the Hans algorithm from tissue biopsy at both diagnosis and relapse. Thirty patients were characterized as GCB DLBCL on initial presentation, and upon relapse 28 were noted to be GCB, while 2 were noted to be the non-GCB subtype. Of the 13 that were characterized as non-GCB on initial presentation, 10 remained non-GCB while 3 were reclassified as GCB. The overall agreement of DLBCL COO phenotypes between initial diagnosis and relapse was 88%. Seven percent of those initially diagnosed as GCB were reclassified as non-GCB subtype; in contrast, 23% of those initially diagnosed as non-GCB had changed to GCB upon relapse. Similar analysis was performed on individual immunohistochemical staining factors including CD10, Bcl-6, and Mum-1, and we observed overall agreement of 88%, 87%, and 91%, respectively. CONCLUSIONS: A majority of patients with relapsed DLBCL exhibit similar COO phenotypes at initial presentation and at relapse, and the incidence of reclassification from one subtype to another is uncommon. This suggests that the initial treatment regimen for DLBCL rarely alters the basic cancer phenotype when immunohistochemistry laboratory technical factors and pathologist interpretive discrepancies are excluded as causes for this change. However, reclassification from GCB to non-GCB subtypes is observed in a minority of cases, which may affect the overall outcome and response to treatment. Further studies are needed using gene expression to categorize COO and to examine the factors surrounding the time of relapse for possible harbingers of relapse as well as the behavior and outcome of reclassified DLBCL. Table Table. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Abstract Background: Peripheral T-cell lymphomas (PTCLs) comprise a group of non-Hodgkin lymphomas (NHLs) of mature T-cell origin with generally aggressive clinical behavior. Most systemic PTCLs are treated with anthracycline-based combination chemotherapy; however, outcomes remain relatively poor for most subtypes except ALK-positive anaplastic large cell lymphoma (ALCL). We have used landmark analyses based on event-free survival (EFS) to identify clinically useful endpoints in B-cell NHLs, with EFS at 24 (EFS24) months identified to stratify overall survival (OS) in aggressive B-cell NHL. Here we examined the ability of EFS24 to predict subsequent OS in a large, multinational PTCL cohort. Methods: A cohort of newly diagnosed PTCL patients treated with curative intent combination chemotherapy regimens was assembled from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), Swedish Lymphoma Registry (SWE), and British Columbia Cancer Agency (BCCA). Subtypes included ALK-negative ALCL, angioimmunoblastic T-cell lymphoma (AITL), PTCL, not otherwise specified (NOS), enteropathy-associated T-cell lymphoma (EATL), extranodal NK/T-cell lymphoma, nasal type (ENKTL), and hepatosplenic T-cell lymphoma (HSTCL). Patients were followed based on local institution guidelines, and EFS was defined as time from the date of pathologic diagnosis to progression, re-treatment, or death due to any cause. EFS24 was defined as being alive and event-free 24 months from diagnosis. Subsequent OS was defined as time from achieving EFS24 (24 months from diagnosis) or time from progression in patients failing to achieve EFS24 (progression within 24 months of diagnosis). OS was compared to the age-, sex-, and country-matched general population using United States, Sweden, and British Columbia rate tables via standardized mortality ratios (SMR) and expected survival. Results: 775 patients diagnosed from 2000-2012 were included in the combined analysis with diagnosis by the WHO classification at the respective institutions (MER=138, SWE=422, BCCA=215). Median age at diagnosis was 64 years (range 18-89) and 63% were male. Patient characteristics are summarized in the table. 736 (95%) received anthracyline-based therapy at diagnosis. At a median follow-up of 77 months (range 1-185), 516 patients (67%) had died. The percentage of patients achieving EFS24 was similar across the 3 cohorts (MER=39%, SWE=35%, BCCA= 36%, combined=36%). Median survival after progression within the first 24 months was only 4.9 months (95% CI: 3.8-5.9), with a 5-year OS of 11% and SMR of 46.4 (95% CI: 41.8-51.3). In contrast, median survival after achieving EFS24 was not reached, with a 5-year OS of 78% (95% CI: 73%-84%). This was inferior to the expected survival of 92% in the age-, sex-, and country matched population (SMR=3.16; 95% CI: 2.48-3.98). In EFS24 subgroup analyses, more favorable outcomes were observed in younger patients (age <=60 years, N=137, 5-year survival of 91% vs. 98% expected) and in patients receiving autologous stem cell transplant in first remission (N=72, 5-year survival of 88% vs. 96% expected). Patients achieving EFS24 who were not transplanted in first remission (N=189) had a 5-year survival of 74% vs. 90% expected. Conclusions: Assessment of EFS24 stratifies subsequent outcome in PTCL. Patients with early relapse from PTCL have extremely poor outcomes. However, over one-third of patients with PTCL remain in remission two years from diagnosis after initial chemotherapy and have encouraging OS rates, although survival remains significantly worse than the matched general population. Subset analysis suggests that younger patients and patients who receive autologous stem-cell transplant in first CR have 5-year survival rates that approach 90%, though still below the expected survival of the background population. The marked differences in OS after failing or achieving EFS24 in PTCL patients suggest that this endpoint may be useful for patient counseling, as a clinical trial endpoint, and as an endpoint to assess novel biomarkers for risk stratification. Table Table. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Maurer: Celgene: Research Funding; Kite Pharma: Research Funding. Jerkeman:Mundipharma: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Celgene: Research Funding. Connors:Seattle Genetics: Research Funding; Millennium Takeda: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Abstract The anti-CD20 monoclonal antibody rituximab (R) is widely used to treat B-cell malignancies including follicular lymphoma (FL). A better understanding of activity and resistance mechanisms is necessary for improving treatment outcomes. We previously reported that genetic variants in the complement pathway are associated with event-free survival of FL patients following R therapy. This correlation was particularly high for SNP rs3766404, located in intron 6 of Complement Factor H (CFH). Subjects with the minor allele of this SNP experienced inferior event-free survival. Five CFH related proteins (CFHR1-5) share a similar and sometimes overlapping function with CFH, including suppression of complement activation. Genetic variations within the CFH family locus are linked to a variety of complement-mediated disorders such as age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome. Interestingly, AMD patients with the minor allele of rs3766404 frequently have deletion of CFHR3 and CFHR1, suggesting that loss of these proteins functionally impacts complement regulation. The current studies were designed to better understand the relationship between R therapy of FL and CFH family proteins. CFH and CFHR1 protein levels were quantified in serum samples from both normal subjects (n=59) and FL (n=108) subjects from the Iowa/Mayo Lymphoma SPORE Molecular Epidemiology Resource. No correlation was observed between the quantity of CFH in serum and SNP genotype in either cohort. However, in both cohorts, individuals homozygous for the minor allele in SNP rs3766404 lacked detectable expression of CFHR1. Homozygotes for the major allele expressed the highest levels of CFHR1, and heterozygotes expressed intermediate levels. Among FL subjects treated with R as a component of initial therapy, increased levels of CFHR1 were associated with improved event-free survival (hazard ratio 0.48, 95% confidence interval 0.28-0.82, p=0.0051). In contrast, CFHR1 levels had no impact on outcome among the FL subjects who did not receive R as a component of initial therapy. This subset of FL subjects included those observed off therapy. The effect of CFHR1 levels on outcome for those subjects treated with R versus those not treated with R was statistically different (p=0.0023 based on a Cox proportional hazard model). There was no correlation between CFH levels and outcome in any population. CFHR1 binds the complement component C3b, inhibiting downstream complement activation. We previously demonstrated that complement can inhibit R activity in vitro. Specifically, C3b deposition can have a negative impact on antibody–mediated tumor cell killing by interfering with R-induced NK cell activation and antibody dependent cellular cytotoxicity. Our current finding that higher CFHR1 correlates with improved outcome following R therapy provides further evidence that the effect of complement on therapeutic monoclonal antibodies is complex. These findings may have implications for predicting response to, and optimization of, anti-CD20 and other antibody therapies. Ongoing studies are exploring this possibility in additional patient cohorts, the potential role of other CFH family members, and the underlying biology associated with these observations. Disclosures: Link: Genentech: Consultancy; Millenium: Consultancy; Pharmacyclics: Consultancy; Spectrum: Consultancy; Genentech: Research Funding; Millenium: Research Funding; Pharacyclics: Research Funding.

Abstract Background. Diffuse large B-cell lymphoma (DLBCL) is curable for the majority of patients treated with anthracycline based immunochemotherapy (IC). While most patients achieve response to initial therapy, a subset of patients are refractory to initial IC or become refractory to subsequent salvage therapies. Prognosis in this setting is very poor. Here we determine the incidence of refractory disease from a large cohort of DLBCL prospectively followed from diagnosis in the IC era and assess outcomes in these patients. Methods. Patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis. Patients were followed for relapse, retreatment, and death; all events were validated by medical record. This analysis includes patients with DLBCL or primary mediastinal B-cell lymphoma (PMBCL) who received initial treatment of anthracycline based immunochemotherapy; patients with primary CNS lymphoma or post-transplant lymphoproliferative disorders were excluded. Response to therapy was retrospectively classified per 2007 Revised Response Criteria for Malignant Lymphoma from available clinical and radiology records. Refractory disease was defined as having a best response to any systemic therapy of stable disease (SD), progressive disease (PD), or relapse within 12 months of autologous stem cell transplantation (SCT). We also examined patients with transient response to IC as defined by achieving an interim response (CR or PR) but having progressive disease at or prior to the end of the planned number of cycles of IC. Results. 1039 patients with DLBCL or PMBCL lymphoma were enrolled in the MER from 2002-2012 and treated with R-CHOP or comparable IC. Median age at diagnosis was 62 years (range 18-91) and 577 (56%) were male. At a median FU of 60 months (range 1-148), 136 patients developed refractory disease. The median age at diagnosis of patients with refractory disease was 62 years (range 19-87). The cumulative incidence of refractory DLBCL was 11.3% at 2 years (95%: CI: 9.5-13.4) and 13.1% at 5 years (95% CI: 11.2-15.4). The median overall survival after becoming refractory was 4.7 months (95% CI: 4.1-5.5) with a 1 year survival rate of 21% (95% CI: 15%-30%). The median number of therapies before becoming refractory was 2 with 35 patients becoming refractory following their first therapy (i.e. IC), 83 patients becoming refractory after their 2nd therapy, and 23 patients becoming refractory after their 3rd or later therapy; 27 patients had received stem cell transplant prior to becoming refractory. Outcomes were poor regardless of when patients became refractory (figure). Patients received a median (range) of 2 (0-8) treatments after becoming refractory with 40% (N=54) attempting subsequent platinum based salvage therapy and 14% (N=9) proceeding to ASCT, of which only 6 remain alive in long-term remission. 41 patients (30%) were treated on clinical trials after becoming refractory. Response rate for the first therapy after becoming refractory was 21%, while 29% of patients had a response to any subsequent therapy. Once patients became refractory, there was no difference in survival based on response at end of initial IC (p=0.33), cell of origin at diagnosis (p=0.64), IPI at diagnosis (p=0.33), or age when refractory (p=0.66). Outcomes in patients with transient response to IC (n=58) were poor, with the majority (N=37, 63%) becoming refractory to subsequent therapy. Median OS after first relapse was 6.7 months in patients with transient response to IC, which was equivalent to patients refractory to IC (p=0.99). The majority of patients with transient response to IC (69%) were next treated with platinum based salvage therapy which had a response rate of 40%. Ultimately 15 of the 58 patients (26%) proceeded to transplant, of which only 5 (9%) achieved long-term remission. Conclusions. Approximately 13% of patients with DLBCL become refractory to treatment in their disease course. Outcomes once patients become refractory are extremely poor regardless of when patients become refractory. Standard prognostic factors are no longer predictive of outcome and stem cell transplant had limited benefit in this group of patients. Patients with transient response to initial immunochemotherapy should be included when classifying patients as refractory. New therapy strategies are needed in the refractory setting. Figure 1. Figure 1. Disclosures Maurer: Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Farooq: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.

Abstract Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease characterized by multiple low-frequency alterations including somatic mutations, copy number alterations (CNAs) and chromosomal rearrangements. We sought to identify previously unrecognized low-frequency genetic events, integrate recurrent alterations into comprehensive signatures and associate these signatures with clinical parameters. For these reasons, our multi-institutional international group assembled a cohort of 304 primary DLBCLs from newly diagnosed patients, 87% of whom were uniformly treated with state-of-the-art therapy (rituximab-containing CHOP regimen) and had long term followup. Tumors were subjected to whole exome sequencing with an extended bait set that included custom probes designed to capture recurrent chromosomal rearrangements. In this cohort, 47% of samples had available transcriptional profiling and assignment to associated disease subtypes. Analytical pipelines developed at the Broad Institute were used to detect mutations (MuTect), CNAs (Recapseq+Allelic Capseq) and chromosomal rearrangements (dRanger+Breakpointer) and assess clonality (Absolute). To analyze formalin-fixed paraffin-embedded tumors without paired normals we developed a method which utilized 8334 unrelated normal samples to stringently filter recurrent germline events and artifacts. Significant mutational drivers were identified using the MutSig2CV algorithm and recurrent CNAs were assessed with GISTIC2.0. In addition, we utilized a recently developed algorithm, CLUMPS2, to prioritize somatic mutations which cluster in 3-dimensional protein structure. With this approach, we identified > 90 recurrently mutated genes, 34 focal amplifications and 41 focal deletions, 20 arm-level events and > 200 chromosomal rearrangements in the DLBCL series. Of note, 33% of the mutational drivers were also perturbed by chromosomal rearrangements or CNAs, underscoring the importance of a comprehensive genetic analysis. In the large DLBCL series, we identified several previously unrecognized but potentially targetable alterations including mutations in NOTCH2 (8%) and TET2 (5%). The majority of identified chromosomal rearrangements involved translocations of potent regulatory regions to intact gene coding sequences. The most frequently rearrangements involved Ig regulatory elements which were translocated to BCL2, MYC, BCL6 and several additional genes with known roles in germinal center B-cell biology. After identifying recurrent somatic mutations, CNAs and chromosomal rearrangements, we performed hierarchical clustering and identified subsets of DLBCLs with comprehensive signatures comprised of specific alterations. A large subset of tumors shared recurrent alterations previously associated with follicular lymphoma including mutations of chromatin modifiers such as CREBBP, MLL2, and EZH2 in association with alterations of TNFRSF14 and GNA13 and translocations of BCL2. This cluster was enriched in GCB-type DLBCLs and contained a subset with select genetic alterations associated with an unfavorable outcome. An additional cohort of tumors was characterized by alterations perturbing B-cell differentiation including recurrent BCL6 translocations or alterations of PRDM1. A subset of these DLBCLs had alterations of NOTCH2 and additional pathway components or mutations of MYD88 in association with TNFAIP3, CD70 and EBF1, a master regulator of B-cell differentiation. An additional group of DLBCLs exhibited frequent MYD88 mutations in association with alterations of CD79B, PIM1, TBL1XR1 and ETV6 and BCL2 copy gain; these tumors were highly enriched for ABC-type DLBCLs. This coordinate signature and additional alterations of p53 pathway components were associated with outcome. We explored bases for the identified genetic alterations in DLBCL by performing an in silico mutational signature analysis. The most frequent mutational signatures were those of spontaneous deamination (aging) and AID with rare cases of microsatellite instability. We also assessed the clonality of identified genetic features to define cancer cell fraction and establish the timing of specific genetic events. The comprehensive genetic signatures of clinically annotated DLBCLs provide new insights regarding approaches to targeted therapy. Disclosures Link: Kite Pharma: Research Funding; Genentech: Consultancy, Research Funding. Rodig:Perkin Elmer: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Pfreundschuh:Boehringer Ingelheim, Celegene, Roche, Spectrum: Other: Advisory board; Roche: Honoraria; Amgen, Roche, Spectrum: Research Funding. Shipp:Gilead: Consultancy; Sanofi: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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. A recent meta-analysis of 9 case-control and 5 cohort studies reported a positive association of transfusion history with risk of NHL (RR=1.20; 95% CI 1.07-1.35), which was only evident in cohort (RR=1.25) and not case-control (RR=1.05) studies (Castillo et al., Blood 2010;116:2897-2907). Risk was similar in men and women, and for transfusions before or after 1992. In subset analyses, elevated risk was only apparent for chronic lymphocytic leukemia (CLL) and not diffuse large B-Cell lymphoma (DLBCL) or follicular lymphoma, but power was low. To further investigate these findings, particularly from studies conducted after 1990, better assess confounding, and address heterogeneity by NHL subtypes, we conducted an individual-level, pooled analysis of 13 case-control studies in the InterLymph Consortium (including 11 studies conducted after 1990; 8 studies were not included in the published meta-analysis). Methods. There were a total of 10,805 cases and 14,026 controls with transfusion data from 13 studies conducted in Europe, North America, and Australia. Transfusion history and other risk factors were self-reported in interviewer-administered or self-administered questionnaires. All risk factor data were harmonized centrally, and cases were grouped into NHL subtypes according to the WHO classification using guidelines from the InterLymph Pathology Working Group. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression, adjusted for age, sex, and study center. Results. The median age at diagnosis was 60 years for cases (range, 18-97) and 59 years for controls (range, 16-97). The overall prevalence of a history of any transfusion in controls was 15.5%, was higher in women (18.6%) than men (13.0%), and increased with age, but was not associated with race/ethnicity (Asian, Black, Hispanic, White, other) or geographic region after adjusting for age and sex. Among whites, history of any transfusion was inversely associated with NHL risk among men (OR=0.74; 95% CI 0.65-0.83) but not women (OR=0.92; 95% CI 0.83-1.03); there were no significant results for other race/ethnicity groups, and ORs were highly variable and imprecise due to small sample sizes. Thus analyses were restricted to white men, where there was no trend with the number of transfusions, time since first transfusion, age at first transfusion, or decade of first transfusion. Further adjustment for socioeconomic status, body mass index, smoking, alcohol use or hepatitis C virus (HCV) seropositivity did not alter these results. The associations were stronger in hospital-based (OR=0.56; 95% CI 0.45-0.70) than population-based (OR=0.84; 95% CI 0.72-0.98) studies, and were stronger in studies from Southern Europe (OR=0.53; 95% CI 0.36-0.79) than northern Europe (OR=0.67; 95% CI 0.53-0.83) or North America (OR=0.82; 95% CI 0.70-0.98). For NHL subtypes, statistically significant inverse associations were observed for follicular lymphoma (OR=0.70; 95% CI 0.56-0.88), DLBCL (OR=0.72; 95% CI 0.59-0.87), and CLL/SLL (OR=0.67; 95% CI 0.52-0.87), whereas weaker and non-statistically significant associations were observed for mantle cell (OR=0.81; 95% CI 0.54-1.23), marginal zone (OR=0.78; 95% CI 0.54-1.15), lymphoplasmacytic (OR=0.82; 95% CI 0.47-1.42) and peripheral T-cell (OR=0.83; 95% CI 0.49-1.40) lymphomas. Conclusion. Contrary to earlier results, transfusion history was inversely associated with risk of NHL and the common subtypes of follicular lymphoma, DLBCL and CLL/SLL among white men, whereas associations were null among white women and other racial/ethnic groups. These results were not explained by confounding by lifestyle factors or HCV seropositivity, era of first transfusion, hospital versus population-based study design, or geographic location. Despite dramatic changes in transfusion practice over the past 40 years, results were similar for decade of first transfusion, suggesting secular trends are a less likely explanation. Our results are unexpected and bias cannot be ruled out. Further studies, particularly cohort studies, are needed to clarify the role of transfusion history in NHL risk. Disclosures No relevant conflicts of interest to declare.