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Abstract BACKGROUND: Infiltration of the spleen plays an important role in the disease progression of patients with chronic lymphocytic leukemia (CLL). Despite this fact, the role for splenectomy in the management of CLL is not well defined. Historically, splenectomy has primarily been used for management of select patients with auto-immune cytopenias (e.g. autoimmune hemolytic anemia [AIHA], immune thrombocytopenic purpura [ITP]). We conducted a retrospective study to evaluate the utility of splenectomy in CLL patients cared for at Mayo Clinic over the last 20 years. METHODS: We used the Mayo Clinic database to identify all CLL patients who underwent splenectomy at Mayo Clinic since 1995. Medical records were reviewed to identify the indications for splenectomy, the pathologic findings at the time of surgery, and clinical outcomes. The indications for splenectomy were categorized as: diagnostic splenectomy, AIHA, ITP, symptomatic splenomegaly, and other. Pathology reports were reviewed to identify the findings at the time of surgery with respect to involvement by CLL and/or other lymphoproliferative disorders. RESULTS: Of the 5333 CLL patients seen at Mayo Clinic between 1/1/1995 and 12/31/2015, 107 (2%) underwent splenectomy at Mayo. The rate of splenectomy in female subjects was 1.7% (31/1779), and the rate in male subjects was 2.1% (76/3554). Of the 2354 subjects with IGHV mutation status, the rate of splenectomy in IGHV mutated subjects was 2.1% (23/1085) compared to 0.7% (9/1269) in IGHV unmutated subjects (p=0.004). The indication for splenectomy in these 107 patients was diagnostic splenectomy in 14 (13.1%) patients, ITP in 22 (20.6%), hemolytic anemia in 19 (17.8%), ITP and hemolytic anemia in 3 (2.8%), symptomatic splenomegaly in 46 (43.0%), and 3 (2.8%) other lymphomas. The rate of splenectomy decreased over the interval of the study (Figure). The per year risk of requiring splenectomy for patients diagnosed with CLL prior to 1995 was 0.32%/year, compared to 0.30%/year for those diagnosed from 1995-1999, 0.24%/year for those diagnosed from 2000-2004, 0.15%/year for those diagnosed from 2005-2009, and 0.16%/year for those diagnosed from 2010-2015 (p=0.01). The indication for splenectomy also changed over the study interval (Table) Pathologic review of the spleen demonstrated normal splenic tissue in 3 (2.8%), infiltration by CLL in 99 (92.5%), involvement by diffuse large B-cell lymphoma in 2 (1.9%) and involvement by other lymphomas in 3 (2.8%; T-cell lymphoma [n=1], T-cell large granular lymphocytic leukemia [n=1], and splenic marginal zone lymphoma [n=1]). CONCLUSION: These findings describe a large experience with the use of splenectomy in patients with CLL. Splenectomy is utilized relatively rarely (2% of CLL patients). The role of splenectomy in the management of CLL also appears to be changing with both a decreased frequency of splenectomy and a change in the indication for splenectomy over the last 2 decades. The potential benefits of splenectomy must be weighed against the know risks such as a lifelong increased risk of infection, as well as a higher risk of thromboembolism and secondary cancers. Splenectomy Indication by Time Period of CLL Diagnosis Table 1 Table 1. Figure 1 Figure 1. Disclosures Parikh: Pharmacyclics: Honoraria, Research Funding. Ding:Merck: Research Funding. Shanafelt:GlaxoSmithkKine: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; Hospira: Research Funding.

Abstract INTRODUCTION: The prevalence of liver dysfunction in patients with previously untreated chronic lymphocytic leukemia (CLL) is unknown; knowledge of which may provide important context for emerging therapeutic options with possible hepatotoxicity. The impact of liver dysfunction on outcomes of CLL patients is not well described. METHODS: Between 09/1993 and 04/2016, previously untreated CLL patients seen in the Division of Hematology at Mayo Clinic at diagnosis (<12 months) and who had baseline assessment of at least one of the following liver function tests (LFTs): alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin were included in this analysis. Baseline lab values were defined as the closest value to CLL diagnosis for each lab within 12 months prior to diagnosis up through 6 months after CLL diagnosis. Patients with at least one abnormal LFT (defined as greater than 1.5 x the upper limit of normal) were classified as having liver dysfunction at diagnosis. Analysis for factors related to baseline liver function was performed using age- and sex-adjusted logistic regression models. Kaplan-Meier methods and multivariable Cox regression analysis was used to evaluate time to first treatment (TTFT) and overall survival (OS). RESULTS: Of 2336 previously untreated CLL patients who met the inclusion criteria, 123 (5%) patients had at least one abnormal LFT value at time of diagnosis. Thirty five patients had abnormal AST (median value 106 U/L, range 72-745 U/L, reference range 8-48 U/L), 25 patients had abnormal ALT (median 112 U/L, range 82-313 U/L, reference 7-55 U/L), and 54 patients had abnormal total bilirubin (median 2.10 mg/dL, range 1.8-26.5 mg/dL, reference range ≤ 1.2 mg/dL). Forty five patients had abnormal alkaline phosphatase; 35 patients in the year 2003 or later (median 198 U/L, range 172-2269 U/L, reference range 45-115 U/L) and 10 patients in 2002 or earlier (median 471.5 U/L, range 394-706 U/L, reference range 98-260 U/L). Abnormal LFTs were more common among those with advanced Rai stage disease (Rai 0-II=4.7% vs. Rai III-IV=13.4%; p<0.001) and among patients with lower hemoglobin (median 13.1 g/dL vs. 13.9 g/dL; p<0.001) at diagnosis. No difference in the rate of abnormal LFTs was observed based on cytogenetic abnormalities detected by FISH or CD38, CD49d, ZAP-70 or IGHV gene mutation status. There was no significant difference in prior alcohol abuse history between patients with liver dysfunction at diagnosis (6%) and those without (5%) (p=0.63). Similarly, there was no significant difference in body mass index between groups (median 27.8 vs. 27.8; p=0.12). After 12 years of follow-up, an estimated 69% of the cases with abnormal LFTs were treated. The most common type of treatments included anti-CD20 monoclonal antibody therapy only, followed by purine nucleoside based chemoimmunotherapy, and an alkylating agent with a monoclonal antibody. The median time to treatment was 4.3 years for cases with abnormal LFTs compared to 6.3 years for cases without abnormal LFTs (p=0.02). However, after adjusting for age, sex and Rai stage, there was no difference in TTFT among patients with abnormal LFTs at baseline compared to those with normal LFTs (hazard ratio [HR] = 1.2 (95% CI, 0.9-1.6); p=0.23). The median survival of CLL patients with abnormal LFTs at diagnosis was significantly shorter than those with normal LFTs (8.6 vs. 11.6 years, p<0.001, Figure 1). After adjusting for age, sex and Rai stage, multivariable cox regression analysis showed that abnormal LFTs retained independent prognostic significance for OS with a HR of 1.4 (95% CI, 1.1-1.8; p=0.012). CONCLUSION: At the time of CLL diagnosis, ~1 out of every 20 patients with previously untreated CLL has abnormal LFTs. These data provide context to the recent reports of hepatotoxicity with the use of signal inhibitors in untreated CLL. Although the presence of liver dysfunction at diagnosis does not seem to predict a shorter TTFT, the OS of these patients is significantly shorter compared to patients who have normal LFTs. Figure 1 Figure 1. Disclosures Ding: Merck: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding. Kay:Pharmacyclics: Research Funding; Tolero Pharmaceuticals: Research Funding; Acerta: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Morpho-Sys: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Shanafelt:Janssen: Research Funding; Pharmacyclics: Research Funding; GlaxoSmithkKine: Research Funding; Genentech: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; Hospira: Research Funding. Parikh:Pharmacyclics: Honoraria, Research Funding.

Abstract Background: One of the main complications in CLL is Richter syndrome (RS). RS derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B-cell lymphoma (DLBCL) type. RS occurs in 2.2% to 8% of patients with CLL and the prognostic is poor with a median survival from 5 to 8 months. Detection of RS by imaging has resulted in conflicting and non-significant results. Aim: The objective of this study was to validate recent findings correlating FDG/PET imaging and histological features in CLL and to demonstrate that a tumoral maximum standardized uptake value > 10 measured on 18F-FDG-PET is a new valid marker to discriminate RS. Results: From June 2006 through December 2012, 240 patients from the Division of hematology of Centre Hospitalier Lyon Sud and Créteil and from the Mayo Clinic Rochester have been analyzed with a mean age of 62 years (21-91). Clinical, histological (confirm by biopsy) and biological parameters have been identified with 10% of the patients as having RS, 34% stable CLL disease; 42% of rapid CLL progression (histological features of progression defined as increased large cell number, large confluent proliferation centers or high proliferation rate assessed by Ki-67 but not meeting criteria for diffuse large B-cell lymphoma/RS) and 14% with others diseases (e.g. infection and or cancers). For patients with stable CLL disease, the median tumoral SUV max was 2 (range: 0-2.4). Among patients with a rapid progression of CLL, 90% had a tumoral SUV max <10 but greater than the liver median SUV max (4.5 range: 1-11). In contrast, 90% of patients with RS had a median tumoral SUV max >10 (12.9; range: 5-27). A statistically significant difference between SUV max of CLL patients with stable disease and RS was observed (2.2 vs. 12.9; p< 0.0001) and similarly for SUV max of CLL patients with rapid disease progression and RS (4.5 vs 12.9; p< 0.0001). Regardless of the RS prevalence (2.2% to 8%), statistical tests identified a threshold of tumor SUV max > 10 as the more discriminating cut off. Using this threshold, the sensitivity and specificity of PET to identify RS in our cohort are 91% and 95% respectively. Assuming an RS prevalence of 2.2%, positive predictive value (PPV) and negative predictive value (NPV) using the >10 threshold were 28.7% and 99.8%; for an 8% prevalence of RS, the PPV and NPV are 60.8 and 99.2% respectively.The proportion of correctly classified patients with RS is more accurate using a threshold of tumoral SUV max > 10 than 5 (2.2% RS prevalence: 94.8% versus 71.8%; 8% RS prevalence: 94.6% versus 73.5%). Finally analysis of the area under the curve (AUC) reveals a value of 0.95 (95% confidence interval: 0.89- 0.99). Recently, Falchi et al, reported on 332 patients with CLL classified as 95 RS, 117 rapid progression and 120 stable disease and demonstrated a strong correlation between histological features and PET imaging. A SUV max ≥10 strongly correlated with a shorter overall survival. Similarly, in our study we have shown excellent sensitivity and negative predictive value estimated at 100%, revealing the ability of 18F-FDG-PET-CT to rule out the diagnosis of RS if the tumor SUV max is less than 10. Conclusion: 18F-FDG-PET-CT is a valuable tool in the diagnostic evaluation of RS for patients with CLL. It is not only useful to identify RS syndrome and guide the site of biopsy but also to identify CLL patients who will experience more rapid disease progression. An SUV max > 10 is the optimal threshold to distinguish RS in CLL. Disclosures No relevant conflicts of interest to declare.

Abstract Background Although hypogammaglobulinemia is a well-recognized complication in patients with chronic lymphocytic leukemia (CLL), its prevalence at the time of CLL diagnosis and association with novel prognostic markers and clinical outcomes are not well understood. Methods All patients seen at Mayo Clinic between 1/1995 - 4/2013 with newly diagnosed CLL (<12 months diagnosis) and who had baseline assessment of serum immunoglobulin G (IgG) were included in this analysis. Baseline demographic and clinical characteristics as well as serum IgG levels measured by either immunoassay or serum protein electrophoresis analysis were recorded. Based on the normal range for IgG at our laboratory, patients with serum IgG<757 mg/dL were classified as having hypogammaglobulinemia. Patients with IgG<757 were also further stratified by terciles (lower tercile: IgG<585 mg/dL; middle tercile: IgG 585-687 mg/dL, upper tercile: IgG 688-756 mg/dL). The relationship between hypogammaglobulinemia at diagnosis and prognostic parameters including immunoglobulin heavy chain (IGHV) gene mutation status, genetic abnormalities detected by fluorescence in-situ hybridization (FISH), and ZAP-70, CD38 and CD49d expression was assessed. Associations of hypogammaglobulinemia with time to first treatment (TTT) and overall survival (OS) was also evaluated. Results Of 1485 patients who met the eligibility criteria, 382 (26%) had hypogammaglobulinemia (median IgG=624 mg/dL) at the time of CLL diagnosis while the remaining 1103 (74%) had normal serum IgG levels (median IgG=1040 mg/dL). Baseline demographic and clinical characteristics of patients with and without hypogammaglobulinemia are shown in Table 1. When patients with hypogammaglobulinemia (IgG<757 mg/dL) were further stratified into terciles, patients in the lower tercile (n=127) were more likely to have advanced Rai stage (III-IV) at diagnosis (15% vs. 6% vs. 4%, p=0.008), be CD49d positive (56% vs. 43% vs. 32%, p=0.01), and have trisomy 12 on FISH testing (29% vs. 24% vs. 9%, p=0.005) compared to patients in the middle (n=127) and upper (n=128) terciles. After median follow-up of 4.2 years, 479 (32%) patients had received treatment for CLL, and 328 (22%) patients had died. The median TTT for patients with hypogammaglobulinemia was 3.8 years compared to 7.4 years for patients with a normal IgG (p-value<0.001). Among patients with hypogammaglobulinemia, the median TTT for patients in the lower, middle, and upper terciles were 1.7, 2.9, and 6.3 years respectively (p-value<0.001, Figure 1). On multivariable analysis that included age, gender, Rai stage, IGHV mutation status, FISH risk category and hypogammaglobulinemia, the following were independently associated with a shorter TTT: advanced (III-IV) Rai stage (hazard ratio [HR] =15.3, p<0.0001); intermediate (I-II) Rai stage (HR=3.0, p<0.0001); unmutated IGHV (HR=2.6, p=<0.0001); and hypogammaglobulinemia (HR=1.5, p=0.02). Conclusion In this large cohort study, approximately one-quarter of CLL patients had a low serum IgG level at the time of diagnosis. High-risk features, including advanced Rai stage and expression of CD49d, were associated with greater risk of hypogammaglobulinemia at the time of diagnosis. Patients with hypogammaglobulinemia at diagnosis had shorter TTT, a finding that persisted after adjusting for other prognostic factors. Evaluation of acquired hypogammaglobulinemia during the course of follow-up among patients who initially had normal IgG levels is ongoing. 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 Chronic lymphocytic leukemia (CLL) can effect renal function in a variety of ways including direct infiltration of the kidney, ureteral obstruction by lymphadenopathy, and treatment related tumor lysis syndrome (uric acid nephropathy). Rarely, CLL has also been reported to be associated with light chain nephropathy, renal amyloidosis, membranoproliferative glomerulonephritis (MPGN), granulomatous interstitial nephritis (GIN), and minimal change disease (MCD). Nearly all the data on the effects of CLL on renal function is at the case report level. We systematically evaluated the prevalence of renal insufficiency at diagnosis as well the incidence of acquired renal insufficiency during follow-up in a large cohort of patients with newly diagnosed CLL to more accurately define the effects of CLL on the kidney and its impact on clinical outcomes. Methods Between January 1995 -February 2013, previously untreated CLL patients seen in the Division of Hematology at Mayo Clinic at diagnosis (<12 months) and who had baseline assessment of serum creatinine were included in this analysis. Patients with serum creatinine (Cr) ≥1.5 mg/dL at baseline were classified as having renal insufficiency at diagnosis. Patients who initially had baseline creatinine <1.5 mg/dL but who developed a Cr≥1.5 mg/dL during the course of their disease were considered to have acquired renal insufficiency. Results Existing renal insufficiency at the time of CLL diagnosis: Of 2047 patients who met the eligibility criteria, 153 (7.5%) patients had renal insufficiency (Cr≥1.5 mg/dL) at the time of CLL diagnosis including 15 (0.7%) with a Cr≥3 mg/dL. Renal insufficiency was also more common among men (9.3% vs. 3.9%; p<0.00001), those with advanced stage disease (Rai 0=7.0%; Rai I-II=6.4%, Rai III-IV=20.2%; p<0.0001), and CD49d positive patients (6.8% vs. 3.8%; p<0.038). Patients with renal insufficiency at diagnosis were also older (median age 72.2 vs. 63.9; p<0.0001). No difference in the prevalence of renal insufficiency at diagnosis was observed based on cytogenetic abnormalities detected by FISH or CD38, ZAP-70 or IGHV gene mutation status. Although renal insufficiency at diagnosis was strongly associated with OS on univariate analysis (p<0.001), no association was observed between renal insufficiency and TTT or OS on multi-variate analysis adjusting for age, sex, and Rai stage. Acquired renal insufficiency during CLL disease course: Among the 1894 patients with normal renal function at diagnosis, 304 (16.1%) acquired renal insufficiency (Cr≥1.5 mg/dL) during the course of their CLL disease course including 43 (2.3%) with peak Cr≥3 mg/dL. In addition to age (older) and male sex, a number of CLL disease characteristics were associated with a higher likelihood of acquired renal insufficiency including: IGHV UM (OR=2.0; p=0.0001), unfavorable FISH (del17p- or 11q-; OR=2.0; p=0.001), and being CD49d+ (OR=1.8; p=0.002), ZAP-70+ (OR=1.6; p=0.004), or CD38+ (OR=1.4; p=0.0.032),. Shorter TTT (p<0.001) and OS (P<0.001) was observed among patients with initially normal creatinine who acquired renal insufficiency (Figure 1A and 1B). On MV analysis adjusting for age, sex, and stage at diagnosis, acquired renal insufficiency remained an independent predictor of TTT (OR=1.77; p=0.001) and OS (OR=2.67; p<0.001). Renal insufficiency and therapy selection After median follow-up of 4.5 years (range 0-18.0), 620 of 2047 (30.3%) patients have progressed to require treatment. Patients with renal insufficiency prior to treatment were less likely to receive purine nucleoside analogue based therapy and more likely to receive single agent alkylator based treatment. Conclusions Approximately 1 in every 13 patients (7.5%) with CLL has renal insufficiency at the time of diagnosis and an additional 16.1% acquire renal insufficiency during the course of the disease. The risk of developing renal insufficiency is associated with a variety of CLL B-cell characteristics and is associated with TTT and OS. Data on causes of acquired renal insufficiency is being abstracted and will be presented at the meeting. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Off Label Use: MK2206 in a phase 1 trial of CLL.

Abstract Introduction Approximately 2-8% chronic lymphocytic leukemia (CLL) patients develop diffuse large B-cell lymphoma (DLBCL, so-called Richter syndrome [RS]) over long-term follow-up. The outcomes of patients with RS are variable and poorly understood. Methods CLL patients seen at Mayo Clinic from January 1995 to April 2013 who developed biopsy-proven DLBCL during follow-up were included in this analysis. Clinical characteristics, therapy and overall survival (OS) of all patients with RS were analyzed. Results One hundred and twenty patients with biopsy-proven RS were identified in the Mayo Clinic database. The median age at diagnosis of RS was 67 years (range, 29-88 years), 87 (73%) were male, and 83 (69%) had received prior CLL therapy. The median duration between diagnosis of CLL and development of RS was 3.8 years (range, 0-34.5 years). Stereotyped B-cell receptors were found in 9/30 (30%) RS patients compared to 219/1294 (17%) non-RS patients (OR=2.1, p=0.07). IGHV4-39 gene usage was present in 2/26 (8%) RS patients compared to 57/1354 (4%) non-RS patients (p=0.3). Of the 30 RS biopsy samples in which Epstein Barr virus (EBV) in-situ hybridization studies were performed, EBV was detected in 7 (23%) patients. After a median follow-up of 5.2 years, 86 (72%) patients have died. Causes of death were as follows: progressive DLBCL (n=46, 53%), progressive CLL (n=2, 2%), infection (n=8, 9%), unknown (n=20, 23%) and other (n=10, 12%). The median OS of the entire cohort was 0.9 years (95% CI, 0.5-1.3 years). Tsimberidou and colleagues proposed a prognosis score (RS score) based on the following variables at the time of RS diagnosis: Eastern Co-operative Group performance status of 2-4, lactate dehydrogenase >1.5 x normal, platelets<100 x 109/L, tumour size >5 cm and >1 prior therapy for CLL. Each parameter was assigned one point, and patients were then assigned to one of four risk groups based on their calculated RS score: 0 or 1, low risk; 2, low-intermediate risk; 3, high-intermediate risk; 4 or 5, high risk. The OS according to the RS score for our group of patients is shown in Figure 1. Median survival in the low, intermediate-1, intermediate-2 and high-risk groups were 2.4 years, 0.7 years, 0.3 years and 0.2 years, respectively (p<0.001). Fifteen (12%) patients received cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) as initial therapy for RS, and 68 (57%) received rituximab in addition to CHOP (R-CHOP). There was no difference in survival among patients who received CHOP compared to R-CHOP (median, 1.8 years. vs. 1.2 years, p=0.5). Twenty-four patients (20%) received non-CHOP-based chemotherapy, and treatment was unknown in 4 (3%) patients. Nine patients (7%) died before definitive therapy could be instituted. Thirteen (11%) patients were able to proceed to stem cell transplantation (SCT): 10 (8%) autologous SCT, 2 (2%) allogeneic SCT and 1 (1%) autologous SCT followed by an allogeneic SCT. Although RS patients who underwent SCT were younger compared to those who did not undergo SCT (median, 59 years. vs. 69 years, p=0.001), no differences in prior CLL therapy or receipt of R-CHOP therapy for DLBCL was noted between the two groups. The median survival of patients who proceeded to SCT was superior compared to those who did not (5.2 years vs. 0.7 years; p=0.005). Conclusion Stereotyped B-cell receptors but not VH4-39 had a suggested evidence of an increased risk of RS in our cohort. Although 90% RS patients received intensive chemotherapy, only 11% patients were able to proceed to SCT. Median survival of RS patients remains dismal at 1 year, and newer therapies are needed to improve outcomes. 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: Our current understanding of CLL biology and optimal therapies is based on clinical trials that have largely enrolled White patient populations. Whether these findings are applicable to Hispanic or non-White patients is unknown but critical to evaluate given the growing numbers of minority patients in the U.S. While retrospective studies have suggested inferior outcomes in non-White patients, prospective data on these disparities are lacking. Patients and Methods: We utilized the Mayo Clinic CLL database to better understand variations in disease characteristics, molecular differences, and treatment selections between non-Hispanic White patients and those not in this category (referred to hereafter as “other race”). After excluding 49 patients with missing diagnosis date and another 490 patients with missing race and/or ethnicity, the remaining 4104 cases within the registry were included in the analysis. Comparisons by race were made using Chi-square or Wilcoxon rank sum tests for qualitative or quantitative variables, respectively. Overall survival (OS) was calculated from diagnosis until death or last known alive date; time to first treatment (TTFT) was calculated from diagnosis until treatment date or date last known to be untreated. OS and TTFT were displayed via Kaplan-Meier plots, and differences in OS and TTFT by race were calculated using log-rank statistics. Individuals who were enrolled in early intervention trials (n=61) were excluded from analyses involving treatment. Results: In total, 4104 CLL patients were identified: 4011 (97.7%) non-Hispanic Whites and 93 (2.3%) other races. Median age at CLL diagnosis was younger for other race patients (59 vs. 63 years; p=0.002), while gender and stage distributions were comparable between both groups. Serum β-2-microglobulin and absolute lymphocyte counts at diagnosis were similar but more other race patients had elevated LDH (29.5% vs. 16.1%; p=0.02). Cytogenetic data by FISH were available for 1884 non-Hispanic Whites and 46 other race patients; poor-risk cytogenetics (17p and/or 11q deletions) were present in 23.9% of other race and 13.5% of non-Hispanic White patients, respectively (p=0.04). No statistically significant differences were observed for CD38, ZAP-70, or IGHV by race TTFT was similar for both non-Hispanic Whites and other race patients (4.6 vs. 5.5 years, respectively; p=0.12). First-line treatment selection was similar for both groups (Table). . With a median follow-up of 12.1 years, median overall survival was 9.3 years for other race and 12.2 years in non-Hispanic White patients (P=0.15; Figure). Conclusions: This prospective data supports the notion that CLL might be biologically different between non-Hispanic White and other race patients with less favorable FISH present in the latter group. Despite the observation that TTFT and type of first therapy are similar between both groups, the trend towards shorter OS in other race patients argues that other factors might contribute to outcome differences, such as disease biology, access to care, co-morbidities, and socioeconomic considerations. Further studies with larger cohorts are warranted. Table: First-line treatment selection among treated individual by racial First-line Treatment Non-Hispanic Whites(n=1875) Other race(n=41) Chemoimmunotherapy Purine analogue-based Alkylator-based 675 (36.0) 495 (26.4) 180 (9.6) 15 (35.6) 9 (22.0) 6 (14.6) Purine analogue -monotherapy 157 (8.4) 4 (9.8) Alkylator monotherapy 610 (32.5) 9 (22.0) PA+Alkylator 41 (2.2) 1 (2.4) Antibody alone 190 (10.1) 6 (14.6) Other 202 (10.8) 6 (14.6) Figure: Overall survival in CLL cases stratified by race Figure:. Overall survival in CLL cases stratified by race Disclosures Nabhan: Genentech: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau. Kay:Celgene: Research Funding. Shanafelt:Genentech: Research Funding; GlaxoSmithKline: Research Funding; Celegene: Research Funding; Cephalon: Research Funding; Pharmacyclics/Jannsen: Research Funding; Hospira: Research Funding; Polyphenon E Int'l: Research Funding.

Abstract Introduction: Several B-cell malignancies, including chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), are known to have a familial component to disease risk. Although several common inherited genetic variants have been found to be associated with risk of these malignancies, a large proportion of the heritability remains unexplained. Here we set out to identify rare high-penetrance susceptibility variants for CLL and MM using the established Mayo Clinic family study of B-cell malignancies. Methods: We performed exome sequencing on germ line DNA of 106 families with either two or more members with CLL (n=93 families) or two or more members with MM or monoclonal gammopathy of undetermined significance (MGUS) (n=13 families) using Aglient capture kits. All samples were sequenced on an Illumina HiSeq2000. Bioinformatics analyses leveraged the following software packages: Novoalign, Picard, The Genome Analysis Toolkit (GATK), and the Biological Reference Repository (bioR). Quality control filters were implemented; subjects with mis-specified relationships were removed as were variants with <95% call rate or <20x coverage, and those variants identified as sequencing artifacts. To identify potentially functional single nucleotide variants, the following was required a) uncommon in public databases, b) cosegregating variants in multiple families, c) variants to be highly conserved and in coding regions, and d) functional prediction status of deleterious (SIFT score), damaging (PolyPhen score), and a moderate, or high variant impact (SNPEffect). The association of these variants with risk was then evaluated in large samples of cases and controls in genome-wide association studies (GWAS). Results: In the CLL familial cohort, there were 443 individuals (160 with CLL, 73 with monoclonal B cell lymphocytosis (MBL), and 210 relatives without CLL or MBL) sequenced; and in the MM cohort, there were 39 individuals (13 with MM, 13 with MGUS and 13 without MM or MGUS) sequenced. A total of 61,992 single nucleotide variants passed quality control filters in the CLL cohort and 39,456 single nucleotide variants in the MM cohort. From these, we identified 32 variants in the CLL cohort and 39 variants in the MM cohort that were cosegregating in multiple CLL or MM families, respectively, and were predicted to affect protein structure or function. Of these, one CLL variant was within 1 Mb of a known GWAS-discovered locus. Moreover, there were seven CLL and four MM variants that were within 1 Mb of single nucleotide polymorphisms (SNPs) that had statistical significance between p<10-4 and p<10-6 in GWAS. Finally, there were 3 variants found to be common between CLL and MM families (see Table). Conclusions: Through whole exome sequencing, we identified a number of rare, highly penetrant predisposition variants for CLL and MM. Several of these variants were common to both B-cell malignancies providing evidence of shared genetic components; one variant may be a functional driver of the GWAS-discovered loci. These identified variants provide a list for future validation studies. Table: Exome variants common in both Chronic Lymphocytic Leukemia and Multiple Myeloma SNP ID rs41314099 rs61754114 rs143025033 Chromosome 17 6 7 Gene WSCD1 BACH2 TNS3 Penetrance (CLL) 0.70 0.75 0.80 Penetrance (MM) 1.00 0.80 0.75 Allele Frequency (CLL) 0.015 0.025 0.017 Allele Frequency (MM) 0.077 0.077 0.058 1000 Genome Frequency (European) 0.010 0.020 0.010 SIFT Term Deleterious Deleterious Deleterious PolyPhen Term Probably Damaging Probably Damaging Probably Damaging SNP: Single Nucleotide Polymorphism; CLL: Chronic Lymphocytic Leukemia; MM: Multiple Myeloma; Penetrance is defined as proportion of individuals carrying the alternate allele that are also affected; SIFT: Sorting Intolerant From Tolerant, predicts whether an amino acid substitution affects protein function; PolyPhen: Polymorphism Phenotyping, predicts possible impact of an amino acid substitution on the structure of a human protein Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 4252 Background: Multiple recent studies have demonstrated the survival benefits of reduced intensity allogeneic stem cell transplant for high risk CLL patients. These transplant series, however, represent highly selected cases where age, co-morbidities and performance status preclude transplant in many patients with CLL. The portion of newly diagnosed CLL patients that are eventually considered for transplant is unknown, as well as the proportion that are referred for transplant evaluation; the proportion that actually receive stem cell transplant, and the reasons for not pursuing transplant in referred patients. We conducted a cohort study of newly diagnosed CLL patients to address this gap in knowledge. Methods: We used the Mayo Clinic database to identify all patients with newly diagnosed CLL seen at Mayo Clinic within 1 year of diagnosis between July of 2003 and May of 2011 (time interval during which reduced intensity allogeneic stem cell transplantation was part of routine care at Mayo Clinic). Electronic medical record and laboratory studies were reviewed to identify all patients referred for stem cell transplant evaluation (either allogeneic transplant for progressive CLL or autologous stem cell transplant for Richter's transformation). Patients referred for transplant were analyzed to determine what proportion completed transplant and, for those who were not transplanted, the reason they were not transplanted (e.g. lack of insurance approval, co-morbidity, lack of a donor, inadequate disease control, death prior to transplant or patient preference). Results: A total of 1250 patients with newly diagnosed CLL between July 2003 and May 2011 who were seen at Mayo Clinic within 1 year of diagnosis were identified. The mean age at diagnosis was 63.6 yrs and 34.2% were women. With respect to disease stage, 48.7% were Rai stage 0, 45.5% Rai stage I/II, and 5.8% Rai stage III/IV. CLL FISH analysis revealed 126 (13.6%) patients who had either del (17p) or del (11q) and 801 (86.4%) patients who had other FISH abnormalities or normal FISH results. After a median follow-up of 41 months, 425 (34%) of patients have received treatment. A total of 54 patients (4.3%) were referred for a transplant evaluation during follow-up. Of these 54 patients, 48 (3.8% overall cohort) were referred for consideration of allogenic transplant for treatment of progressive CLL and 6 (0.5%) were referred for autologous transplant for treatment of Richter's transformation. Baseline characteristics associated with subsequent transplant referral included age at diagnosis (median: 56 yrs) (p &lt; 0.0001, Odds Ratio (OR) for each year older = 0.91, 95% Confidence Interval (CI)=(0.88, 0.95)), Rai stage (III/IV vs. 0) (p = 0.0002, OR = 22.7, 95% CI=(5.1, 102.4)) and FISH (del(11q), del(17p) vs Normal, del(13q) or Trisomy 12) (p &lt; 0.0001, OR = 7.3, 95% CI=(3.3, 16.1)). Gender, Rai stage (I/II vs. 0), and patient residence (local vs. not local) were not significant. Among the 54 patients referred for transplant, 28 (51.9%) completed a transplant. This included 22 (45.8%) patients referred for allogenic transplant and 6 (100%) patients referred for autologous transplant. Among the 26 patients referred who did not undergo transplant, the principal reasons were patient preference (n = 6, 23.1%), patient still being evaluated for transplant as of the study end date (n = 6, 23.1%), alternative therapy chosen (n = 5, 19.2%), inadequate disease control (n = 3, 11.5%), death prior to transplant (n = 3, 11.5%), lack of insurance approval (n = 2, 7.7%), and lack of a donor (n = 1, 3.8%). Conclusion: 4.3% of the newly diagnosed CLL patients in this series were considered for stem cell transplant at some point during follow-up. Young age, high Rai stage and high risk FISH abnormalities are principal reasons for transplant referral. Only 51.9% of those considered for transplant completed transplant. The principal reasons for referral patients not completing transplant who had adequate time to follow were patient preference, alternative therapy, inadequate disease control and death prior to transplant. The remaining 6 patients (23%) are in process of transplant evaluation with longer follow required. These analyses provide first incidence data for CLL transplant referral in a cohort of newly diagnosed patients. Disclosures: Zent: Biothera: Research Funding; Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; GlaxoSmithKlime: Research Funding. Shanafelt:Celgene: Research Funding; Teva/Cephalon: Research Funding; GlaxoSmith Klein: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Polyphenon E International: Research Funding.

Abstract Abstract 3903 The clinical utility of 2-deoxy-2-[18F] fluoro-D-glucose (FDG) positron emission tomography-computed tomography (PET-CT) scans in the management of patients with chronic lymphocytic leukemia (CLL) has not been clearly defined. CLL cells typically have low FDG avidity and the addition of the PET component has not been shown to improve the utility of CT scans in the management of patients with CLL. However, patients with CLL are at increased risk of developing FDG avid complications including more aggressive lymphomas, other second malignancies, and infections for which FDG PET-CT scans are a useful imaging modality. We hypothesized that FDG PET-CT scans are sensitive tests for evaluation of these complications in patients with CLL. Patients and Methods: This observational study was performed with IRB approval. We studied all 4030 CLL patients seen at least once in the Division of Hematology at Mayo Clinic Rochester between January 1, 2006 and December 31, 2011 using data prospectively collected into the Mayo Clinic CLL database. We reviewed the clinical and radiological records of the 272 (7%) patients who underwent 526 FDG PET-CT scans of the trunk during this time period to determine the indication for PET-CT scan, results of imaging, and the effects of the use of PET/CT scan on management. Results: Four hundred and seventy two (90%) of the 526 PET-CT scans were reported as abnormal. Of these, 78 (17%) scans were useful in directing a tissue biopsy of high FDG avidity lesions. Of the 37 (8%) positive PET-CT scans that facilitated the diagnosis of new complications of CLL, 21 (4%) scans led to a diagnosis of diffuse large B cell lymphoma and 9 (2%) scans led to a diagnosis of a solid malignancy. The FDG component of 22 PET-CT scans done because of clinical suspicion of complications of CLL were negative, and thus useful in management of these patients. PET-CT scans showed progressive CLL in 138 (29%) studies but in these patients, the PET component of the scan did not provide additional information about the status of the patients' CLL compared to the CT component alone. Conclusions: FDG PET-CT scans are not of proven value in staging CLL or determining response to treatment. However, our data suggest that they could be of considerable value in evaluation for complications, especially more aggressive lymphomas, other cancers, and infections that complicate the course of CLL. Disclosures: Off Label Use: Phase I study using PGG beta glucan in CLL. Zent:Biothera: Research Funding; Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding.