Slager, Susan L.

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

Abstract Abstract 1546 Background: Follicular lymphoma (FL) is an incurable disease with an undefined optimal management strategy. Global priorities in goals of care are avoidance of death and transformation to aggressive subtypes. Retrospective series, – most including patients diagnosed before ubiquitous rituximab use, - describe diverse rates of transformation with a common consensus of 3% per year, and with a median survival post transformation of less than 2 years. This study sought to characterize transformation events in a prospective observational series begun after diffusion of early rituximab use in FL. Methods: Newly diagnosed FL patients were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) from 2002–2009. Clinical data were abstracted from medical records using a standard protocol. Patients were actively followed for retreatment, transformation, and death. Inclusion criteria for this analysis were initial diagnosis of grade I-IIIa FL. Exclusion criteria for this cohort include composite diffuse large B-cell lymphoma (DLBCL), FL grade IIIb, or evidence of clinical or pathological transformation at the time of FL diagnosis. Transformation was defined as refractory/recurrent disease with either a) biopsy confirmed subtype of FLIIIb, DLBCL or higher grade B-cell lymphoma; or b) clinical indication of transformation (sudden rise in LDH, rapid discordant localized nodal growth, new involvement of unusual extranodal sites, new B symptoms or hypercalcemia). Risk of transformation was analyzed via time to transformation using a death as a competing risk. Time to transformation was defined as the date of initial FL diagnosis to date of transformation. Overall survival was defined as the date of initial diagnosis to date of death or last known follow-up for patients still alive. Results: There were 631 newly diagnosed grade I-IIIa FL patients with a median age at enrollment of 60 years (range 23–93). 54% were male. The most common types of initial therapy were observation (33%), rituximab (R) monotherapy (12%), alkylator based chemotherapy +/− R (22%), and anthracycline based chemotherapy +/− R (20%). At a median follow-up of 60 months (range 11–110), 79 patients had died, 311 patients had an event (death, progression, or retreatment), and 60 patients (9.5%) had transformed. Transformation was biopsy proven in 48 of the 60 patients (80%). The overall transformation rate at 5 years (TX5) was 10.7% (95% CI: 8.3%–13.8%) (Figure 1). Time to transformation was associated with a FLIPI score of 3–5 (HR=2.37, 95% CI 1.28–4.39, p=0.006), but was not significantly associated with other standard clinical characteristics. Risk of transformation was different in the common initial treatment groups with the highest rate in patients who were initially observed (TX5=14.4%) and lowest rate in patients who initially received R monotherapy (TX5=3.2%)(p=0.058). Outcome after transformation was inferior to MER subjects with de-novo diagnosed DLBCL (p<0.0001). The median overall survival from date of transformation was 44 months (95% CI: 22-NA). Survival after transformation was superior in patients who transformed greater than 18 months after FL diagnosis compared to patients who transformed earlier (5 yr OS =70% vs 20%) (p=7 ×10−5), and for those initially observed (median unreached) versus those patients who were initially treated with alkylator or anthracycline based chemotherapy (median survival of 11 months)( p=0.016). Conclusions: Follicular transformation rates in this modern large prospective observational study are similar to risk of death without transformation and slightly lower at 5 years than most previous reports. Post-transformation prognosis is substantially better than described in older series. These observed differences may be a function of the prospective nature of the study design, modern management strategies, or patient selection factors. Initial management strategies may influence the risk of transformation. Marked survival differences following early vs. late transformation suggest that these may be different biologic events. Disclosures: Link: Genentech: Consultancy, Research Funding; Celgene: Consultancy; Millenium: Consultancy. Johnston:Novartis: Consultancy.

Abstract Background: It is well established that the incidence of skin cancers in patients with CLL are significantly elevated compared to age- and sex- matched controls. However, little is known about the characteristics of CLL patients who develop skin cancer. Herein, we evaluate the associations of CLL clinical and prognostic characteristics, along with UV radiation exposure, with risk of first skin cancer following CLL diagnosis. Methods: Newly diagnosed CLL patients from Minnesota, Iowa, and Wisconsin were enrolled in the Mayo Clinic case-control study from 2002-2015 and systematically followed in the Iowa/Mayo Lymphoma SPORE. Clinical and prognostic CLL data were obtained from the Mayo Clinic CLL database, and skin cancer clinical data were abstracted from medical records using a standard protocol. The CLL international prognostic index (CLL-IPI) was computed using a weighted average of five independent CLL prognostic factors (IGHV mutational status, serum b2-microglobulin, Rai stage, age, and FISH 17p deletion/TP53 status). Self-reported history of midday sun exposure at various ages (birth to age 12; 13 to 21 years; 22 to 40 years, and 41+ years) was obtained from a risk factor questionnaire. For each age, we asked the extent of mid-day sun as: practically no exposure (under 3 hours per week), little exposure (4-7 hours per week), moderate exposure (8 to 14 hours per week) and extensive exposure (15+ hours per week). Midday sun exposure was modeled as an ordinal covariate. To evaluate associations with risk of skin cancer following CLL diagnosis, we calculated time from date of CLL diagnosis to date of first skin cancer, death, or last known follow-up. We used Cox regression analysis to estimate hazard ratios (HRs) and 95% CIs. CLL treatment was considered a time-dependent covariate. Results: Among 846 CLL patients enrolled, the median age at diagnosis was 63 years (range 28-91), 68% were male, 7% had Rai stage III-IV at diagnosis. Based on the CLL-IPI, 42% were categorized as low risk, 33% as intermediate risk, and 25% as high or very-high risk. 109 CLL cases (13%) had one or more reported skin cancers at or prior to CLL diagnosis. Melanoma was observed in 19 (2%) cases and non-melanoma was in 90 (11%) cases. At a median follow-up of 7 years from CLL diagnosis, 165 patients (20%) had one or more skin cancers after CLL diagnosis. Among these patients, 49 had skin cancer before CLL diagnosis. The most frequent skin cancer was squamous cell carcinoma (59%), followed by basal cell (31%), melanoma (5%), and Merkel cell (1%). 552 (65%) of the 846 patients returned a questionnaire. Significant associations of clinical and prognostic characteristics with risk of first skin cancer were observed for age (HR=1.35 per 10 year increase, 95% CI=1.17-1.56, P<0.001), male sex (HR=1.38, 95% CI 0.98-1.96, p=0.07), prior history of skin cancer (HR=4.19, 95% CI=2.98-5.88, P<0.001), and CLL-IPI (HR=1.26, 95% CI= 1.03-1.54, P=0.026, after adjusting for age, sex, and prior skin cancer). Of note, the risk of first skin cancer in those CLL patients categorized as very high via CLL-IPI had 2.28 fold risk (95% CI 1.02-5.11). Midday sun exposures for each of the ages considered showed no evidence of association with risk of first skin cancer (all P>0.05). 50 CLL patients were treated prior to first skin cancer following CLL diagnosis; we observed no evidence of association between treatment and risk of first skin cancer (HR=1.44, 95% CI= 0.93-1.92, P=0.12). Conclusion: CLL patients who are at an increased risk of skin cancer following CLL diagnosis are those who either have had a prior history of skin cancer or a more aggressive CLL disease at diagnosis, according to CLL IPI. Routine skin cancer screening is currently recommended for CLL patients. Our data suggest that more frequent screening would be particularly important among patients with aggressive CLL and who have a prior history of skin cancer. Unexpectedly, we found no evidence of association of skin cancer risk with UV radiation following CLL diagnosis or with CLL treatment. Further investigation is needed to determine whether other factors increase the risk of skin cancer following CLL diagnosis. Disclosures Shanafelt: Genentech: Research Funding; GlaxoSmithkKine: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding.

Abstract Abstract 2902 Background: Although chronic lymphocytic leukemia (CLL) is a low grade B-cell malignancy, 2–8% of patients (pts) are reported to undergo transformation to diffuse large B-cell lymphoma (DLBCL; Richter's syndrome [RS]). Whether the risk of transformation is related to the underlying biology of CLL or is a consequence of treatment for CLL is uncertain. Also, the role of prognostic markers such as immunoglobulin heavy chain (IGHV) gene mutation status, ZAP-70 and CD38 expression, and genetic abnormalities detected by fluorescence in situ hybridization (FISH) in predicting the development of RS is not well defined. The available data on stem cell transplant (SCT) in pts with RS is based on retrospective case series of selected RS pts and is of uncertain relevance to the majority of CLL pts experiencing RS. Therefore, we conducted a cohort study of newly diagnosed CLL pts to explore the incidence and natural history of RS. Methods: The Mayo Clinic CLL database includes all consenting pts with a pathologic diagnosis of CLL. Information on date of diagnosis, treatment history, and disease-related complications is abstracted from clinical records on all pts and then maintained prospectively. We used this database to identify newly diagnosed pts with CLL from January 2000 through July 2011, who were seen at our institution within 12 months of diagnosis. Pts with biopsy-confirmed RS were included in this analysis. For pts referred from an outside institution, pathology review at Mayo Clinic was mandatory to be included in this study. The Mayo Clinic Institutional Review Board approved the study. Results: Between January 2000 and July 2011, 1641 pts with newly diagnosed CLL were seen at Mayo Clinic within 12 months of diagnosis, and this cohort had a median follow-up of 4.0 yrs (range, 0–12.3 yrs). Of these pts, 37 (2.3%) were diagnosed with RS. The median time to development of RS after a diagnosis of CLL was 1.8 yrs (range, 0–11.7 yrs). The incidence of RS at 2 and 5 yrs post CLL diagnosis were 1.3% and 2.1% respectively (Figure). Pts who developed RS had more advanced (Rai III/IV) stage disease (22% vs. 6%; p<0.001) and higher beta 2-microglobulin levels (median 3.1 mg/dL vs. 2.3 mg/dL; p=0.003) at diagnosis of their CLL compared to pts without RS. Pts who developed RS were also more likely to be positive for ZAP-70 (58% vs. 33%; p=0.03), CD49d (77% vs. 31%; p=0.0004), and CD38 (57% vs. 29%; p=0.001), have unmutated IGHV (76% vs. 44%; p=0.003) and have either del(11q22.3) or del(17p13) on FISH analysis (46% vs. 13%; p<0.0001). RS transformation occurred prior to treatment of CLL in 17 (46%) pts and after treatment of CLL in 20 pts (54%). Treatment for CLL was associated with an increased risk of RS (92% vs 34%; p<0.0001). The odds ratio (OR) of RS was increased for pts who received purine nucleoside analogues (OR=3.0; 95%CI=[1.6, 5.9]; p=0.001), alkylating agents (OR=2.5; 95% CI=[1.3, 4.9]; p=0.004), or both (OR=3.3; 95% CI=[1.7, 6.4]; p=0.0003) for treatment of their CLL. Median overall survival after development of RS was 2.1 yrs. Most pts (29/37, 78%) received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. Two (5%) pts underwent an autologous SCT and 5 (14%) underwent an allogeneic SCT. Additionally, 1 (3%) patient received an autologous SCT followed by an allogeneic SCT. By the end of the study period, 17 (46%) pts with RS had died. Conclusion: The overall rate of biopsy-proven RS in this large cohort of pts with newly diagnosed CLL was 2.3% (5 year incidence: 2.1%). Clinical characteristics (Rai stage III/IV) and biologic characteristics of the CLL B-cell (positive expression of ZAP-70, CD38 and CD49d; unmutated IGHV; and either del(11q22.3) or del(17p13) on FISH) at the time of diagnosis were associated with future risk of RS. Exposure to purine nucleoside analogues and/or alkylating agents for treatment of CLL was also associated with increased risk of RS. Disclosures: Zent: GlaxoSmithKline: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Genzyme: Research Funding; Biothera: Research Funding. 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: Chronic lymphocytic leukemia (CLL) remains a heterogeneous disease despite significant advances in disease classification based upon cellular and molecular markers. Rai stage, immunoglobulin heavy chain variable region mutation status (IGHV), cytogenetic abnormalities, beta 2 microglobulin levels, expression of ZAP-70, CD38 and CD49d provide useful guides alone or in prognostic models for progression risk assessment but variability in clinical outcome in early Rai stage (Rai 0/I) unmutated (UM) IGHV patients persists. This variability in clinical outcome suggests that there are yet-to-be defined biologic/genetic factors that contribute to disease heterogeneity. Long non-coding RNAs (lncRNAs) display a range of diverse activities including regulation of gene transcription, post translational regulation and epigenetic regulation and represent an intriguing prospect for influencing CLL disease progression. LncRNAs have been implicated in diagnosis, prognosis and therapy of various cancers however their role in influencing disease progression in early Rai stage UM CLL has not yet been studied. Methods: To investigate a role for lncRNAs in UM Rai 0/I CLL patients we employed the Arraystar Human lncRNA Microarray v4.0. Using blood samples collected within 3 months of diagnosis, two cohorts of UM Rai 0/I patients were compared: one defined as progressive disease with time to first treatment (TTT) ≤ 2 years after diagnosis (n=34) and one as indolent disease with TTT ≥5 years after diagnosis (n=29). Differentially expressed lncRNAs were identified using Agilent GeneSpring GX Software v12.1. To be considered for further analysis, the difference in lncRNA expression had to have a fold change (FC) ≥ 2.0, a t-test p-value ≤ 0.05 and a false discovery rate (FDR) ≤ 0.05. Results: Over 1100 lncRNAs were found to be differentially expressed between the progressive and indolent UM CLL cohorts. Greater than 150 of these lncRNAs have known associated genes and are well annotated and validated. Among the differentially expressed lncRNAs, several are of particular interest and potentially relevant to CLL disease biology. For example, the lncRNA AL833181 was overexpressed in the progressive group. The associated gene for AL833181 is BCL11A and encodes a zinc finger protein that interacts with BCL6 and may itself serve as a proto-oncogene. Translocations involving BCL11A have been shown to identify a very aggressive subset of CLL (Am J Pathology, 2009). Therefore it is possible this lncRNA may be playing a role in deregulated expression of BCL11A. Within the indolent disease group, CTD-2566J3.1 was overexpressed >10-fold as compared to the progressive disease group. Its associated gene RAD51B is essential for DNA repair, suggesting the possibility that CTD-2566J3 may protect CLL cells from further DNA damage and disease progression. Also overexpressed in the indolent disease group were 2 lncRNAs that are associated with genes that encode proteins involved in the ubiquitin-proteasome system. USP2-AS1 lncRNA is associated with the USP2 gene and encodes an ubiquitin-specific protease required for TNF-alpha induced NF-kB signaling and is a specific deubiquitinase for cyclin D1, a known proto-oncogene. Furthermore, USP2-AS1 may also be linked to MYC. RP11-522I20.3 is associated with the QBLN1gene which encodes a protein that mediates the proteasomal degradation of misfolded or accumulated proteins. Thus, the associated lncRNAs may be acting as post-transcriptional gene silencers. Although CLL is not viewed as an "invasive" cancer, there were 5 lncRNAs overexpressed in the indolent group that are associated with Ankyrin genes which play a role in cell motility, activation and proliferation along with the lncRNA RP11-477D19 that is associated with theTIAM2 gene. TIAM2is a Rac guanine nucleotide exchange factor that can promote invasion and motility of cells. The respective lncRNAs may be down-regulating these genes and prohibiting malignant cell expansion. Conclusions: Our study reveals that there are indeed specific lncRNAs that are expressed at different levels in progressive versus indolent early Rai stage UM CLL and have the potential to impact a number of relevant biological processes and pathways. While these data are preliminary, the lncRNA AL833181 and its associated gene BCL11A may prove to be a potential marker and therapeutic target for aggressive disease. Disclosures Shanafelt: Pharmacyclics: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; GlaxoSmithkKine: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Hospira: Research Funding.

Abstract Abstract 149 Background. There are few established factors that predict risk of follicular lymphoma (FL) transformation, and only two studies have evaluated the role of germline genetic variation and risk of transformation. One study reported an association of a BCL6 SNP (397C>G) with risk of transformation, and a second study reported an association with rs6457327, which is in the HLA region of 6p21. This study evaluated the risk of FL transformation in the modern treatment era with germline SNPs that were previously reported to be associated with FL transformation (BCL6SNPs and rs6457327), along with SNPs (N=45) previously associated with either risk of FL or FL prognosis. Methods. Newly diagnosed FL patients were prospectively enrolled from 2002–2009 into the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma SPORE. Peripheral blood for genotyping was collected at enrollment, and clinical and treatment data were abstracted from medical records. All patients were actively followed for disease progression, retreatment, transformation and death. For this analysis, only FL patients with grade I-IIIa were included. Patients with composite DLBCL, FL grade IIIb, or other evidence of transformation at diagnosis were excluded. Transformation was based on either 1) biopsy confirmation of FL grade IIIb, DLBCL, or higher grade B-cell lymphoma; or 2) clinical indicators of transformation based on the published literature, including sudden rise in LDH, rapid discordant localized nodal growth, new involvement of unusual extranodal sites, new B-symptoms, or hypercalcemia. Genotyping was conducted using a custom Illumina iSelect panel. Cox regression was used to estimate Hazard Ratios (HRs) and 95% confidence intervals (CI) for individual SNPs with time to transformation, 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 631 newly diagnosed grade I-IIIa FL patients, of whom 532 had DNA and were successfully genotyped. The median age at diagnosis was 60 years (range 23–93) and 53% were male. FLIPI distribution was 42% 0–1, 34% 2 and 24% 3–5. Initial therapies included observation (32%), rituximab (R) monotherapy (13%), alkylator-based chemotherapy +/− R (20%), and anthracycline-based chemotherapy +/− R (19%). At a median of 59 months of follow-up (range, 11–110), 58 patients died, 254 had an event (death, progression or retreatment) and 54 patients (10%) transformed. Transformation was biopsy proven in 43 of the 54 patients (80%). The SNP rs6457327 on chromosome 6p that was previously reported to be associated with transformation was positively associated with risk of transformation in our data (HR=1.40; 95%CI 0.97–2.04; p=0.07), although this association was weaker but still consistent with the prior report. Further, we evaluated additional typed SNPs from the HLA region of 6p, and found additional associations (p<0.05) with HLA-DRA (3 SNPs), HLA-DQA2 (2 SNPs), HLA-DOA (2 SNPs) and HLA-DPB1/HLA-DPA2 (2 SNPs), of which rs10484569 from HLA-DPB1/HLA-DPA2 was the most strongly associated with risk of transformation (HR=3.01; 95%CI 1.48–6.09; p=0.002). None of the BCL6 or other previously reported risk SNPs were associated with transformation. Of the SNPs previously associated with FL prognosis, only the FCGR2A rs1801274 (HR=1.41; 95%CI 0.94–2.10; p=0.09) and CD46 (CD46 molecule, complement regulatory protein) rs2466571 (HR=1.72; 95%CI 1.16–2.55; p=0.007) were associated with risk of transformation. For CD46, one additional SNP (rs2796269) was also associated with transformation (HR=0.61; 95%CI 0.40–0.95; p=0.03). Further adjustment for FLIPI score and treatment (observation versus all other) did not alter these associations. Conclusions. The previously reported association of rs6457327 with risk of transformation in the modern treatment era was replicated. In addition, several HLA loci and two FL prognosis SNPs were linked to transformation risk. The remaining published FL risk or prognosis SNPs were not associated with transformation. Our results support a role for germline genetic variation in the HLA region, FCRGR2A and CD46 in transformation of FL. Disclosures: No relevant conflicts of interest to declare.

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 INTRODUCTION: Among patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the indications for liver biopsy are not known. Additionally, the histopathologic findings of CLL infiltration in the liver along with its clinical implications have not been thoroughly described in the literature. METHODS: We identified all pts with a diagnosis of CLL/SLL from the CLL Clinical Database at Mayo Clinic, Rochester, MN who underwent a liver biopsy. We also cross referenced the Mayo Clinic Hematopathology Database for all pts who underwent a liver biopsy. The indications for biopsy, description of the pathologic findings in the liver biopsy, CLL therapy and outcomes were abstracted from the clinical records. Retrospective pathology review was performed on cases with CLL involvement in which slides were available for review. RESULTS: Fifty-two CLL/SLL pts who underwent a liver biopsy were identified. The indications for liver biopsy were as follows: liver lesion identified on radiographic imaging in 21 (41%) pts, abnormal liver function tests (LFTs) in 17 (33%) pts, hepatosplenomegaly in 11 (21%) pts, and unknown in 3 (6%) pts. Among all 52 pts, there was concern for Richter transformation at time of biopsy in 7 (13%) pts. Types of biopsy were as follows: percutaneous in 20 (39%) pts, intraoperative in 17 (33%) pts, transjugular in 3 (6%) pts, and unknown in 12 (23%) pts. CLL/SLL involvement was identified in 38/52 (73%) pts undergoing liver biopsy. Among these, the diagnosis of CLL/SLL was made on liver biopsy in 8 pts, and 7 pts had additional findings on their liver biopsy including metastatic colon cancer (n=3), hemochromatosis (n=2), steatohepatitis (n=1), and cirrhosis (n=1). Liver biopsy revealed Richter transformation in 4 (8%) pts (3 pts with diffuse large B cell lymphoma (DLBCL) and 1 patient with Hodgkin lymphoma), other malignancy in the absence of CLL in 7 (15%) pts (2 metastatic colorectal, 2 metastatic esophageal, 1 hepatocellular carcinoma, 1 metastatic lung, and 1 neuroendocrine), and 1 patient with steatohepatitis. Two (4%) pts had normal findings on liver biopsy. Among the 38 pts with liver involvement by CLL, 27 had slides available for retrospective pathology review. CLL involvement ranged from 2-100% of the liver parenchyma. Seven pts (26%) underwent excisional biopsies or resections and 20 (74%) underwent core biopsies. The portal tracts were the most common region of the liver involved (22/26 pts, 85%). Of these, 8/22 (36%) pts had extension into the lobules or sinusoids, as well. Of the 4 cases without portal involvement, 2 showed extensive involvement such that it effaced the liver parenchyma in the region of involvement. One patient (4%) had a predominantly sinusoidal involvement. One patient (4%) showed small nodular infiltrates that were difficult to localize due to their size. Proliferation centers were noted in only 3 pts (11%). Most pts (29/38; 76%) whose liver biopsy demonstrated involvement by CLL did not receive immediate CLL-specific treatment. Nine of the 38 pts (24%) with CLL involvement on liver biopsy received therapy (Table): purine analog based therapy (n=4), rituximab and steroids (n=2), steroids only (n=1), alkylator and rituximab (n=1), and ibrutinib (n=1). Pts with extensive involvement of the liver by CLL were more likely to receive purine nucleoside analog based therapy compared to pts with portal infiltration by CLL (2/2 pts [100%] vs. 1/6 pts [17%]). The remaining pts were offered no therapy due to incidental finding of CLL in the liver biopsy (n=11), chemotherapy for other cancer (n=5), palliative care (n=3), or unknown (n=10). Pts with Richter's transformation received R-CHOP (n=2) and CHOP (n=1) for DLBCL, and ABVD (n=1) for Hodgkin lymphoma. Pts with other cancers without CLL received appropriate therapy for their underlying malignancy. CONCLUSION: Abnormal LFTs and radiographic abnormalities were the most common indications for a biopsy in this large cohort of CLL pts. Infiltration of the portal tracts by CLL/SLL was the most common histopathological finding. Proliferation centers were not commonly seen, which may make the diagnosis challenging for the pathologist if there is not a prior history of CLL/SLL. The mere presence of CLL/SLL infiltration did not mandate treatment and many pts were able to continue observation. Table Table. Disclosures Ding: Merck: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding. Shanafelt:GlaxoSmithkKine: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding. Parikh:Pharmacyclics: Honoraria, Research Funding.