Citations

Abstract Introduction: The Food and Drug Administration (FDA) approved ibrutinib in February 2014 based on results from a pivotal phase 2 clinical trial that enrolled 85 patients with relapsed/refractory CLL. A subsequent phase 3 trial confirmed the superior progression-free survival (PFS) and overall survival (OS) of ibrutinib compared to ofatumumab in 391 CLL patients. However, there is no information on the efficacy and safety of ibrutinib in CLL patients treated outside the context of clinical trials. Additionally, it is unclear if the reasons for discontinuation of ibrutinib differ in routine clinical practice from those described in patients treated on clinical trials. We conducted a retrospective study to evaluate these aspects in a large cohort of CLL patients treated with ibrutinib off-protocol. Methods: After IRB approval, CLL patients seen at Mayo Clinic, Rochester, MN, and treated with commercial ibrutinib from November 2013 through July 2015 were evaluated. The baseline characteristics, time to therapy discontinuation, reasons for discontinuation and survival following discontinuation were abstracted. Results: One hundred thirty-five patients with CLL were treated during the study interval; 124 received ibrutinib for relapsed/refractory CLL and 11 received ibrutinib for treatment-naïve CLL with TP53 disruption (either del17p on FISH or TP53 mutation). Patients with relapsed/refractory CLL (n=124) Patients were high-risk, with a median of 3 prior therapies (range, 1-15), 81% had unmutated IGHV, and 38% had either del11q or del17p on FISH testing. After a median follow-up of 6.4 months, 101 remain on ibrutinib therapy. The estimated proportion of patients continuing ibrutinib at 6 months was 84% (95% CI: 77-92%) and at 12 months was 70% (95% CI: 59-83%). Of the 23 who discontinued ibrutinib therapy, 8 discontinued for progressive disease (2 progressive CLL; 6 Richter's transformation). The remaining 15 discontinued therapy for reasons other than progression, including: infection (n=3), bleeding (n=3), diarrhea (n=1), atrial fibrillation (n=1), rash (n=1), immune thrombocytopenia (n=1), renal dysfunction (n=1), severe edema (n=1), MDS (n=1) and physician preference (n=2). Table 1 shows the reasons for discontinuation of ibrutinib in patients treated on clinical trials (Maddocks, JAMA Oncology, 2015) compared to the current cohort of patients. The estimated cumulative incidence of discontinuation of ibrutinib therapy due to CLL progression/Richter's transformation at 6 and 12 months was 9% (95% CI: 4-17%) and 12% (95% CI: 5-23%), respectively. The estimated cumulative incidence of ibrutinib discontinuation due to reasons other than progression at 6 and 12 months was 10% (95% CI: 5-17%) and 22% (12-34%), respectively (Figure). The median survival after discontinuation of ibrutinib for patients who had CLL progression was 3.5 months, not reached in patients who developed Richter's transformation and not reached in those patients who discontinued ibrutinib due to reasons other than progression. Patients with treatment-naïve CLL (n=11) All patients had evidence of TP53 disruption (9 had del17p, 3 had TP53 mutation, and 1 had both). After a median follow-up of 2.8 months, no patient has had progression of CLL, and 2 patients have discontinued ibrutinib therapy for reasons other than CLL progression (atrial fibrillation, n=2). The estimated proportion of patients continuing ibrutinib at 6-months was 71% (95% CI: 45-100%). All 11 are still alive, and no patient has undergone allogeneic stem cell transplantation. Conclusion: This is the first study that describes the outcomes of a large cohort of CLL patients treated with ibrutinib outside the context of clinical trials. Patients treated in routine practice appear more likely to discontinue ibrutinib for reasons other than progression of disease, compared to those participating in clinical trials. Our results confirm the poor survival of CLL patients who progress on ibrutinib. Table 1. Comparative analysis of reasons for discontinuation of ibrutinib in patients with relapsed/refractory CLL: Characteristic Current Study (%) Maddocks (JAMA Oncology 2015) (%) No. of patients 124 308 Median follow-up (months) 6.4 20 Reasons for Discontinuation Progression of disease CLL 2 (2) 13 (4) Richter's transformation 6 (5) 15 (5) Non-progression of disease Infection 3 (2) 28 (9) Other 12 (10) 17 (5) Figure 1. Figure 1. Disclosures Ding: Merek: Research Funding. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Tolero Pharm: Research Funding. Shanafelt:Cephalon: Research Funding; Celgene: Research Funding; Glaxo-Smith_Kline: Research Funding; Polyphenon E Int'l: Research Funding; Hospira: Research Funding; Janssen: Research Funding; Pharmactckucs: Research Funding; Genentech: Research Funding.

Abstract Abstract 4610 Introduction: Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). Up to 50% of patients with CLL will develop infectious complications during the course of their disease, and 30–50% of all deaths from CLL are attributed to infections and infectious complications. The risk of infection in CLL is related to immune deficiencies associated with the primary disease process, as well as immunosuppression secondary to treatment. Available research on infectious complications of CLL has focused on patients in clinical trials receiving chemotherapy. Little is known about the natural history of infection in community dwelling patients with newly diagnosed CLL. Method: To explore the natural history of infection in a local, community dwelling cohort of patients diagnosed with CLL, we used the Mayo Clinic CLL database to identify all patients with newly diagnosed CLL seen in the Mayo Clinic Division of Hematology after January 1, 1999 and who resided within 50 mi of Mayo Clinic (Rochester, MN). All patient hospitalizations were reviewed to document infection including cross-referencing with the electronic Mayo Clinic infection database which includes all culture and serology results obtained from hospitalized Mayo Clinic patients. Patients who had positive blood, sputum, cerebrospinal fluid, pleural fluid, or paracentesis fluid culture results were identified. Patients whose cultures were negative were considered to have culture negative infection. Serologies and viral assays (e.g. CMV viral load) were also reviewed to identify infections. Results: In May 2010, there were 2022 patients in the Mayo Clinic CLL Database with the diagnosis of CLL/SLL made between Jan 1999 – Dec 2009. Of these, 336 (17%) patients resided within a 50 mi radius of Mayo Clinic and were considered non-referred, community-based CLL patients. Median age at diagnosis for these 336 patients was 69 yrs (range 27–97) and most had early stage CLL (57% stage 0; 34% stage I-II). With respect to prognostic markers, 206 (70%) patients were CD38 negative, 125 (64%) ZAP-70 negative, 85 (53%) IgVH mutated, and 101 (63%) had either no abnormality or 13q14- as a sole abnormality on FISH analysis. Consistent with being a community dwelling cohort, ~90% (152/165) of patients had co-morbid health problems and ~50% (86/165) had a major comorbidity (e.g. coronary artery disease, cerebral vascular disease, CHF, diabetes, COPD, other malignancy). Although ~17% (43/249) of patients had gamma-globulin levels below the reference range at diagnosis, only 2% (6/249) had an IgG level <500 mg/dL. Median follow-up for all patients was 49 months (range 0–121) and 104 (31%) patients progressed to require treatment for CLL. Although 222 (66%) patients required hospitalization during follow-up, only 38 (11.3%) were hospitalized with infection. Collectively, these 38 patients were hospitalized for infection 139 times (median 2 hospitalizations for infection per patient). Among these 38 patients, 13 had no organism identified on cultures (culture negative infection) while the remaining 25 (66%) had an organism identified during at least hospitalization for infection. Of the 38 patients hospitalized with infection, 18/38 (47%) had a gram positive organism (8 strep pneumonia, 11 staphylococcus Aureus, 2 nocardia), 11/38 (29%) had a gram negative organism (3 E.Coli, 4 Pseudomonas, 4 Hemophilus influenzae), 5/38 (13%) a mycobacterial infection (4 MAC, 1 M. gordonae), 15/38 (40%) a cytomegalovirus infection, 19/38 (50%), cryptococcus and/or cryptosporidium (18 cryptococcus AG, 4 cryptosporidium), and 12/38 (32%) a filamentous fungi infections (12 aspergillous). In aggregate, hospitalization for an opportunistic infection (e.g. cytomegalovirus, cryptococcus, filamentous fungi, myocobacteria, pneumocystis) occurred in 26/336 (8%) CLL patients during follow-up. Being male (OR 2.7; p=0.02), ZAP-70+ (OR 3.9; p=0.004), IGHV unmutated (OR 5.5; p=0.002), and receiving treatment (OR 4.7, p<0.001; Figure) were associated with increased risk of hospitalization for infection. Conclusions: Approximately 8% of newly diagnosed, community dwelling CLL patients will require hospitalization for opportunistic infection at some point during the course of their disease. Gender, disease factors (e.g. ZAP-70, IGHV status), and treatment characteristics are associated with infection risk. Disclosures: Zent: Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; G.S.K.: Research Funding. Shanafelt:Celgene: Research Funding; Hospira: Research Funding; Genentech: Research Funding.

Abstract Abstract 2408 Purpose: Vitamin D insufficiency is common globally and in the United States. Approximately 25–50% of patients seen in routine clinical practice have vitamin D levels below the optimal range with low levels linked to higher cancer incidence. Although vitamin D insufficiency is also related to inferior prognosis in some cancers, no data exists for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Patients and Methods: To test the hypothesis that vitamin D levels predict outcome in patients with CLL, we evaluated the relationship of 25 (OH)D serum levels with time-to-treatment (TTT) and overall survival (OS) in 390 newly diagnosed CLL patients participating in a prospective cohort study (discovery cohort) and separate cohort of 153 previously untreated patients participating in an observational study (confirmation cohort). 25 (OH)D levels were measured by liquid chromatography-tandem mass spectrometry. Intra- and inter-assay coefficients of variation were all <7% (data not shown). All vitamin D assays were performed on stored research samples; results were not included in the clinical record and were not known to the treating physicians in either study. Vitamin D insufficiency was defined as a serum 25 (OH)D level <25 ng/mL (62.5 nmol/L), an accepted level3 for the establishment of hypovitaminosis D and the threshold used in routine clinical practice to identify individuals with 25 (OH)D insufficiency by our laboratory in routine clinical practice (http://www.mayomedicallaboratories.com). Results: We evaluated the relationship of 25 (OH)D serum levels with time-to-treatment (TTT) and overall survival (OS) in newly diagnosed CLL patients participating in a prospective cohort study (discovery cohort) and a separate cohort of previously untreated patients participating in an observational study (confirmation cohort). Of 390 CLL patients in the discovery cohort, 119 (30.5%) were 25 (OH)D insufficient. 25 (OH)D insufficiency had no relationship with CD38, ZAP-70, CD49d or IGHV mutation status and had no relationship with FISH risk category as classified using the Dohner system. After median follow-up of 3 years, TTT (hazard ratio [HR]=1.66; p=0.005) and OS (HR=2.39; p=0.01) were shorter for 25 (OH)D insufficient patients (figure). We next attempted to validate these findings in an independent group of previously untreated CLL patients. In the validation cohort, 61 of 153 patients (39.9%) were 25 (OH)D insufficient. After median follow-up of 9.9 years, TTT (HR=1.59; p=0.05) and OS (HR 1.63; p=0.06) were again shorter for 25 (OH)D insufficient patients. On pooled multivariable analysis of patients in both cohorts adjusting for age, sex, stage, CD38, ZAP-70, IGHV, CD49d, and FISH, 25 (OH)D insufficiency remained an independent predictor of TTT (HR=1.47; p=0.008). On multivariable analysis for OS, the HR for death associated with 25 (OH)D insufficiency was similar to univariate findings although the p value did not reach the threshold of statistical significance (HR=1.47; 95% CI=0.97–2.23; p=0.07). Conclusion: 25 (OH)D insufficiency is associated with inferior TTT and OS in CLL patients. Whether normalizing vitamin D levels in deficient CLL patients would improve outcome merits clinical testing. Disclosures: Zent: Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; G.S.K.: Research Funding.

Abstract Background: PRCA is characterized by severe normochromic normocytic anemia, reticulocytopenia, and markedly reduced bone marrow erythroid precursors with intact leukocytic and megakaryocytic lineages. There is limited information about the prevalence and outcomes of PRCA in CLL, with the vast majority of information derived from case reports and small series comprising <10 patients. Here, we describe the clinical features, therapy, and outcomes of CLL patients with PRCA seen at our institution. Methods: The Mayo Clinic CLL Database includes all patients with a diagnosis of CLL evaluated at Mayo Clinic Rochester, MN between January 1995 and December 2014. We identified patients diagnosed with PRCA per the following diagnostic criteria: those who presented with normocytic anemia, had decreased erythroid precursors on bone marrow examination, and reticulocytopenia that could not be explained by any other cause besides PRCA. The baseline demographics, clinical characteristics, therapy, and outcomes were abstracted from the electronic medical records. We generated descriptive statistics and calculated overall survival (OS) from diagnosis date (PRCA, autoimmune cytopenia [AID], or CLL) to last known alive or death date. OS was plotted using Kaplan Meier curves and compared between groups using log-rank statistic. The Mayo Clinic IRB approved this study. Results: Of the 3945 CLL patients seen during the study interval, we identified 30 patients who met the diagnostic criteria of PRCA as described in the Methods section. The baseline characteristics, etiology and therapy for PRCA are shown in Table 1. The median time to PRCA from CLL diagnosis was 4.5 years (range-0.1-14 years). Of the 13 patients with IGHV results available, 12 (92%) were IGHV unmutated. Twenty-one (70%) were male and their median age at PRCA diagnosis was 67 years (range 40-81 years). Parvovirus testing was positive in 6 of 24 (25%) patients who were tested; 3 of these patients were treated with IVIG, 2 were treated with prednisone and IVIg, and 1 was treated with prednisone and rituximab. Eight patients (27%) had both PRCA and autoimmune hemolytic anemia (AIHA), and 1 patient (3%) had concomitant PRCA and immune thrombocytopenia (ITP). Of the 27 patients for whom we have treatment data, 10 required only one treatment regimen and 17 required 2-6 treatment regimens, with two patients requiring splenectomy for concomitant AIHA. The median survival of CLL patients after a diagnosis of PRCA was 4.6 years (Figure 1). There was no difference in survival between PRCA cases with and without parvovirus (p=0.92). Compared to newly diagnosed CLL Rai stage III/IV patients, there was no difference in OS (p=0.53). There was no statistically significant difference in survival from an AID cytopenia diagnosis when comparing PRCA, ITP, AIHA, and Evans syndrome (Figure 1; median 5 years for PRCA and 6 years for other groups; p=0.17). Conclusion: PRCA is a rare complication in CLL, occurring in <1% CLL patients seen at our institution over the past 20 years. Parvovirus was the etiologic factor in ~25% of patients and did not influence outcomes. There appears to be no significant difference in outcomes of PRCA patients compared to patients with other AID in CLL. Table 1. Patient Characteristics Characteristic N [range] or (%) Number of patients 30 Males 21 (70) IGHV status* · Unmutated · Mutated 12 (92) 1 (8) FISH results at CLL diagnosis* · 17p- · 11q- · Trisomy 12 · 13q- · Negative 0 (0) 1 (10) 3 (30) 3 (30) 3 (30) At PRCA Diagnosis Median age 67 [40 - 81] Median hemoglobin (gm/dL)* [normal range 12-15.5 gm/dL] 8.2 [3.5 - 10.8] Median absolute reticulocyte count (x 109/L)* [normal range: 38 - 113 x 109/L] 3.5 [0.0 - 25.3] Patients treated for CLL prior to PRCA diagnosis 25 (83) Etiology of PRCA Parvovirus (n = 24) 6 (25) Therapy-related: · Fludarabine · Alemtuzumab/rituximab · Pentostatin/cyclophosphamide/rituximab 3 (10) 1 (3) 1 (3) Autoimmune (neither therapy nor parvovirus related) 19 (63) Initial Therapy of Non-Parvovirus Related PRCA Steroids alone 2 (8) Steroids and Rituximab 3 (13) Steroids in combination with: · IVIG, Chlorambucil · Cyclosporine · Rituximab, IVIg · IVIg, splenectomy 1 (4) 2 (8) 1 (4) 1 (4) Monoclonal Ab alone · Alemtuzumab · Rituximab 1 (4) 4 (17) Cyclosporine 1 (4) Cyclophosphamide 2 (8) RCP (Rituxan, Cyclophosphamide, and prednisone) 2 (8) IVIg 1 (4) Not available 3 (13) *Not available for all patients Figure 1. Figure 1. Disclosures Ding: Merck: Research Funding. Kay:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Tolero Pharma: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Shanafelt:Cephalon: Research Funding; Hospira: Research Funding; Glaxo-Smith-Kline: Research Funding; Genentech: Research Funding; Jannsen: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding; Pharmacyclics: Research Funding.

Abstract Abstract 1232 Poster Board I-254 B-Chronic Lymphocytic Leukemia (CLL) shows a strong familial risk and also co-aggregates with other indolent lymphomas. Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic hematologic condition characterized by small B-cell clones, most with a surface phenotype similar to that of chronic lymphocytic leukemia (CLL). These clones are detectable at low absolute lymphocyte cell (ALC) numbers in otherwise healthy individuals using sensitive 6 or 8 color flow cytometry analysis and can be a precursor to CLL. In the general population, MBL increases with age with a prevalence of 5% in individuals over age 65. In contrast, the rate of MBL is 13-18% in first degree relatives of CLL patients in high risk families. In the largest study to date, we report the characteristics of MBL among 430 first-degree relatives of CLL patients (with no associated lymphoproliferative diseases [LPD]) in 132 high risk families. Patients and Methods Individuals studied came from “high risk” families (defined as those with two or more confirmed cases of CLL) that are participating in the Genetic Epidemiology of CLL Consortium. Multi-parameter flow cytometry analysis with a detection sensitivity of 0.02% was performed on either fresh or cryopreserved PBMC and MBL was classified according to previously published criteria (Marti et al, Br. J Haematol 130:325, 2005). Both the ALC and the absolute B cell count (B-ALC) were calculated for each individual. Survival analysis was used to compute the probability of developing MBL with age using the life table method. Results The overall rate of MBL was 17% (73/430) among first–degree relatives but the probability for developing MBL by age 90 was 51%. Males had a slightly higher (but non-significant) risk for MBL than females. MBL patients had significantly higher ALC and B-ALC than did those with normal immunophenotype. The mean ALC was 2.5×109/L among MBL patients, and 20% had an ALC greater than 3 ×109/L. The B-ALC count averaged 0.51 ×109/L. Ninety percent of the MBL cases had a CLL-like phenotype (CD20dim, CD5+, CD23+). Conclusions MBL is found at a very high rate in families selected for having 2 or more patients with CLL suggesting that MBL reflects inherited predisposition to CLL. Although most of the MBL cases in these families had low cell counts and thus have a presumed low likelihood of progressing to CLL or other LPD, a higher proportion of them had lymphocytosis compared to those with normal immunophenotype. We hypothesize that if MBL is an early step in the process of development of CLL, then germ line genes are likely to be acting early in carcinogenesis with more “hits” required before CLL develops. By looking for genes associated with MBL or CLL in families or in the population, we could substantially increase our power to identify germ line genes predisposing to CLL. Disclosures Kay: Biogenc-Idec, Celgene, Genentech, genmab: Membership on an entity's Board of Directors or advisory committees; Genentech, Celgene, Hospira, Polyphenon Pharma, Sanofi-Aventis: Research Funding.

Abstract Background Severe cytopenias in CLL are typically associated with bone marrow failure due to massive infiltration of the bone marrow by leukemic cells and negatively impact patient morbidity/mortality. Although near complete marrow replacement by CLL is typically observed in patients whose degree of cytopenia meet criteria for advanced Rai stage disease (Hg<11g/dL; platelet <100 x10^9/L), profound variability in the degree of cytopenia and the extent of marrow infiltration exists, and the relationship between these dimensions is not well characterized. Methods We used the Mayo Clinic CLL database to identify all previously untreated CLL/SLL patients who underwent bone marrow biopsies. CLL patients known to have autoimmune-based cytopenias were excluded from this study. Hemoglobin, platelets, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and absolute monocyte (AMC) at the time of bone marrow biopsy were collected. Characteristics from bone marrow biopsy including marrow cellularity, % CLL involvement, CLL leukemic index (calculated as % cellularity times % CLL), and non-CLL leukemic index (calculated as % cellularity times (1-% CLL)) were also collected. Bone marrow cellularity and % CLL involvement were recorded in the Mayo Clinic CLL database based on clinical estimates made by Mayo hematopathologists. Clinical characteristics and CLL prognostic factors (e.g., Rai stage, CLL FISH, IGHV, ZAP-70, CD38 and CD49d) were also obtained from the database. Age- and sex-adjusted Pearson correlations between the bone marrow measurements and hemoglobin and platelet levels were computed, and scatterplots were created. Results A total of 695 untreated CLL patients diagnosed between 1972 and 2015 who had a CBC test at the time of bone marrow biopsy performed at Mayo Clinic were identified. Median age at diagnosis was 61 years, and 487 (70%) patients were men. Mean time from CLL diagnosis to bone marrow biopsy was 2.2 years. At the time bone marrow biopsy was performed, 20% of patients had advanced stage disease (Rai III/IV) disease, while 44% and 36% had intermediate (Rai I/II) and early stage (Rai 0), respectively. With respect to prognostic parameters, 53% had unmutated IGHV and 20% had high risk CLL FISH (11q- and 17p-). The distribution of other prognostic factors included 43% CD49d+, 35% CD38+, and 42% ZAP-70+ CLL diseases. Median peripheral blood counts were: hemoglobin 13g/dL, platelet 167,000/mL, ALC 26,600/mL, ANC 4100/mL, AMC 700/mL. The median bone marrow cellularity and percent CLL involvement were 70% and 70%, respectively. The median CLL leukemic index was 42%, and median non-CLL leukemic index was 21%. Pearson correlation analysis of bone marrow measurements with peripheral blood hemoglobin found the strongest correlation with the CLL leukemic index (r= -0.49, p<0.001) (Figure), followed by the % marrow CLL involvement (r= -0.45, p<0.001), cellularity (r= -0.40, p<0.001), and non-CLL leukemic index (r= 0.37, p<0.001). Pearson correlation analysis of the bone marrow measurements with platelet count also found the strongest correlation with the CLL leukemic index (r= -0.39, p<0.001), followed by % marrow CLL involvement (r= -0.38, p<0.001), non-CLL leukemic index (r= 0.35, p<0.001), and cellularity (r= -0.28, p<0.001). The peripheral blood ANC levels did not correlate with the four bone marrow measurements. Age- and sex-adjusted Pearson correlations between the bone marrow measurements and hemoglobin and platelet levels were similar to the above unadjusted results. Conclusion To our knowledge, this is the first study to examine the relationship between peripheral blood counts and the extent of bone marrow infiltration in patients with CLL. Although the bone marrow leukemic index had the strongest correlation with peripheral blood Hg and platelet counts, the correlation was modest with an r value of -0.49. These findings suggest that the extent of infiltration of the bone marrow by CLL cells only partially explains of the anemia and thrombocytopenia observed in CLL, indicating other biologic interactions between CLL B-cells and hematopoietic cells contribute to anemia and thrombocytopenia in these patients. More research is needed to determine the nature of these interactions. Disclosures Ding: Merek: Research Funding. Kay:Genentech: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharm: Research Funding. Shanafelt:genentech: Research Funding; Glaxo-Smith-knine: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Hospira: Research Funding; Polyphenon E Int'l: Research Funding.

Abstract Abstract 1268 Poster Board I-290 Purpose There are reports of an increased risk of skin cancers in patients with B-Chronic Lymphocytic Leukemia (CLL). These skin cancers include basal cell and squamous cell carcinoma. This analysis was performed to more completely define the prevalence of skin cancers in patients in the Mayo Clinic Rochester CLL database and to look for contributing factors. Methods The Mayo Clinic Rochester CLL Database includes all patients with a diagnosis of CLL since January 1995 seen in the Division of Hematology and who have signed institutional review board approved consents for research. For this study, 2240 patients were analyzed to compare differences in characteristics between CLL patients with and without skin cancer. Chi-square statistics were used to compare qualitative variables (age categories, gender, referral status, ALC categories, CD38, ZAP-70, IgVH gene mutation status, FISH categories, Rai stage), and t-tests were used for quantitative variables (age at diagnosis, ALC values). Overall survival (OS) and time to first treatment (TFT) analyses were performed with results being displayed using Kaplan-Meier curves and p-values calculated using a log-rank test. Prevalence of melanoma among CLL patients was compared to the age-adjusted prevalence of melanoma in individuals in the Iowa SEER registry. Results Median follow-up for the 2240 patients diagnosed between 1/1/1995 and 8/11/2009 was 4.6 years. In aggregate, 293 (13.1%) patients were found to have non-melanoma skin cancer (squamous cell carcinoma or basal cell carcinoma) cancer. The diagnosis of non-melanoma skin cancer occurred before the CLL diagnosis in 39% and at or after the diagnosis of CLL in 61%. There were 57 (2.5%) cases of melanoma in association with CLL. The diagnosis of melanoma occurred before the CLL diagnosis in 38% and at or after the diagnosis of CLL in 62%.The prevalence of non-melanoma skin cancer and melanoma skin cancer were both higher in non-referred (geographically regional) CLL patients than referred CLL patients (16.6% vs. 11.4%, p<0.001 for non melanoma; 2.0% vs. 3.6%, p=0.03 for melanoma). The prevalence of melanoma in CLL patients was higher than that of age-adjusted prevalence for individuals in the Iowa SEER registry (2.5% vs. 0.03%; p<0.001). We next evaluated the relationship between CLL patients with skin cancer and demographic characteristics, prognostic parameters, and CLL related treatment. The risk of non-melanoma skin cancer in CLL was found to be associated with age (median age at diagnosis with skin cancer 67.6 vs. without skin cancer 63.3, p<0.001) and with sex (males 15.1% vs females 8.9%, p <0.001). There was no statistical significant difference in frequency of non-melanoma skin cancer associated with absolute lymphocyte count (ALC), Rai stage, CD 38, Zap 70, IgVH gene mutation status, FISH, or treatment history. The risk of melanoma in CLL was found to be associated with age at diagnosis (median age with melanoma 69.9 vs. without melanoma 63.8, p=0.002) and CD38 (positive 1.3% vs negative 3.1%, p=0.03). There was no statistically significant difference associated with gender, ALC, Rai stage, Zap 70, IgVH gene mutation status, FISH, or treatment history. Since the presence of skin cancer could be a marker of immune dysregulation we hypothesized skin cancer may be associated with clinical outcome of CLL. Accordingly, we evaluated the relationship between non-melanoma skin cancer and melanoma skin cancer and TFT and OS. Contrary to our hypothesis, TFT (median 6.0 years vs. 4.9; p=0.04) and OS (median 10.8 years vs. 9.7; p=0.02) of patients with non-melanoma skin cancer were both longer than those without non-melanoma skin cancer. No differences in TFT (p=0.06) or OS (p=0.66) were observed among patients with melanoma compared to those without melanoma. Conclusions We find in our cohort of CLL patients a higher prevalence of melanoma than the general population. Risk of melanoma and non-melanoma skin cancer among patients with CLL does not appear to be related to CLL characteristics, with the exception of CD 38, or CLL outcome. The diagnosis of melanoma and non-melanoma skin cancer in patients with CLL does not appear to be a risk factor for either CLL specific outcomes (TFT) or shorter survival. Disclosures Kay: Biogenc-Idec, Celgene, Genentech, genmab: Membership on an entity's Board of Directors or advisory committees; Genentech, Celgene, Hospira, Polyphenon Pharma, Sanofi-Aventis: Research Funding. Zent:Genentech, Bayer, Genzyme, Novartis: Research Funding. Shanafelt:Genentech: Research Funding; Hospira: Membership on an entity's Board of Directors or advisory committees, Research Funding; Polyphenon E International: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Bayer Health Care Pharmaceuticals: Research Funding.

Abstract Abstract 2409 Background: Serum free light chain (FLC) quantitation has prognostic value in MGUS, multiple myeloma (MM), solitary plasmacytoma, and amyloid light chain (AL) amyloidosis, and it has been incorporated in response criteria for both MM and AL amyloidosis. Two recent studies have shown FLC abnormalities are present in 39–54% of CLL patients and are associated with shorter time to treatment (TTT) and inferior overall survival (OS) in CLL. Here we report the largest study to date of FLC abnormalities in a prospective cohort of CLL patients and explore the effects of both monoclonal and polyclonal FLC elevations. Methods: Newly diagnosed CLL patients were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER). Serum FLC was quantitated from stored research serum samples using the Freelite FLC assay (The Binding Site, Ltd., Birmingham, UK). Elevated FLC was defined as either kappa or lambda above the reference range (k>19.4 mg/L, l>26.3 mg/L). Monoclonal FLC elevation was defined as elevated FLC with an abnormal FLC ratio. Polyclonal FLC elevation was defined as elevated FLC with a normal FLC ratio (0.26–1.65). Patients with normal FLC but abnormal FLC ratio were evaluated as a distinct group (Abnormal FLC Ratio). Clinical data was abstracted using a standard protocol for the MER and patients were followed systematically for TTT and OS. Cox proportional hazards models were used to assess the association of FLC with TTT and OS. Results: 385 CLL patients diagnosed between September 2002 and February 2008 with available serum were assayed. At a median follow-up of 47 months (range 1–94), 135 patients (35%) have been treated and 43 patients have died (11%). Abnormalities in FLC were present in nearly half of the CLL patients (48.8%). Although 32.4% had an elevated kappa or lambda, only 14.0% had a monoclonal FLC elevation while the remaining 18.4% had a polyclonal FLC elevation. An additional 16.4% had an abnormal ratio without elevated FLC. Monoclonal FLC elevation was associated with high risk features of CD38+, CD49D+, ZAP70+, IGHV unmutated and having high risk FISH (del 17p13; del 11q22). Monoclonal FLC elevation was highly associated with shorter TTT (HR=3.24, p=0.0007) and poor overall survival (HR=4.14, p=0.0006). These associations remained statistically significant after adjusting for stage and prognostic factors. Abnormal FLC ratio without elevated FLC was also associated with shorter TTT (HR=1.74, p=0.03), though this association did not hold after adjustment for stage and prognostic factors. Polyclonal FLC elevations were associated high risk FISH and poor overall survival (HR=6.41, p<0.0001, adjusted HR = 4.82, p=0.0002) but not with TTT. Conclusions: In the largest series of newly diagnosed CLL patients reported to date, nearly half of CLL patients have abnormal FLC concentrations. Monoclonal FLC elevation is an independent predictor of shorter TTT and inferior overall survival in CLL, is associated with high risk markers, and may be a marker of an aggressive tumor. Polyclonal FLC elevation without abnormal FLC ratio is independently associated with poor overall survival but not TTT suggesting it may be a non-specific marker of host frailty/comorbidity rather than disease specific outcomes. Regardless of cause, CLL patients with elevated FLC have poor outcome and FLC may have utility as a biomarker in CLL. Disclosures: Zent: Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; G.S.K.: Research Funding.

Abstract Abstract 2443 Background: There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association (GWA) study of CLL identified genetic variants located on chromosomes 2q13, 2q37.1, 6p25, 11q24, 15q23, and 19q13 that increased the risk of CLL within a European population. We replicated 5 of these 6 loci in an independent sample of CLL cases and controls from the United States. We now investigate whether these loci also influences MBL, a reported precursor condition of CLL. In addition, a follow-up analysis of the initial GWA study identified four more CLL-susceptibility loci on 2q37.3, 8q24.21, 15q21.3, and 16q24.1. Herein, we also evaluate the association of these four loci with risk of CLL. Methods: Peripheral blood samples were obtained from three ongoing studies: the Genetic Epidemiology CLL (GEC) Consortium, the Mayo Clinic non-Hodgkin lymphoma (NHL)/ CLL study, and the Mayo Clinic Biobank. We implemented rigorous genotyping quality-control measures, and successfully genotyped a total of 407 CLL patients, 965 controls, and 60 MBLs from these studies. Within each locus, the previously reported single nucleotide variants (SNPs) or variants in high linkage disequilibrium (LD) with the previously reported SNPs were evaluated with risk of MBL or CLL. Tests for association was done using the Cochran-Armitage trend test, and unconditional logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for CLL or MBL risk Results: In our evaluation of the six initially reported CLL-susceptibility loci (2q13, 2q37.1, 6p25, 11q24, 15q23, and 19q13) with MBL risk, we found three of the six had suggestive associations (p-value < 0.20) with ORs comparable to and in the same direction as those observed from CLL risk. Our strongest finding was with rs13397985 at locus 2q37.1 (OR= 1.56; 95% CI: 1.05, 2.31; p-trend = 0.041), followed by rs17483466 at locus 2q13 (OR= 1.49; 95% CI: 0.99, 2.24; p-trend = 0.074). As expected given our previously reported findings with CLL risk, the association between rs11083846 on chromosome 19q13 and MBL risk was not significant (p-trend = 0.70). Of the four recently reported CLL-susceptibility loci SNPs located on 2q37.3, 8q24.21, 15q21.3, and 16q24.1, we found all to be associated with CLL risk but one. Specifically, the strongest association was seen for locus 8q24.21 (best tagged SNP rs1021955; OR = 1.37; 95% CI: 1.10, 1.70; p-trend = 0.005), followed by locus 16q24.1 (best tagged SNP rs305065; OR= 0.77; 95% CI: 0.61, 0.97; p-trend = 0.024). However, we found no associations for locus 15q21.3 for the previously reported SNP nor for any SNPs in LD with the previously reported SNP. Conclusions: Our MBL results provide additional robust genetic evidence that MBL is a precursor to CLL and that it shares similar underlying genetic predisposition. Also our results confirm three of the four recently reported CLL-susceptibility loci and further support the role of a genetic basis in the etiology of CLL. More research is needed to elucidate the potential manner in which these genetic loci function in CLL or MBL. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4610 Introduction Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). Up to 50% of CLL patients develop infectious complications, and 30–50% of all deaths in CLL patients are attributed to infections. Despite these data, the available research on infectious complications in CLL is primarily limited to patients participating in clinical trials of chemotherapy, obscuring the distinction between the risk of infection due to the disease’s natural history relative to the risk associated with therapy related immune suppression. METHODS: The Mayo Clinic Rochester (MCR), a tertiary referral center in rural southeastern Minnesota, is also the primary hematology center for southeastern Minnesota, northern Iowa, and western Wisconsin. There are no metropolitan areas or hematology specialty centers within a ∼50 mile radius. To explore the natural history of infection in a community-based cohort of CLL patients, we used the Mayo Clinic CLL database to identify all patients with newly diagnosed CLL who resided within 50 miles of MCR and diagnosed between January, 1999 and December, 2009. The comparison cohort consisted of 689 adult patients who also resided within 50 miles of MCR who were seen for a general medical examination between September, 2002 and December, 2009 and who were enrolled as controls in a case-control study of non-Hodgkin lymphoma. All hospitalizations at MCR among both cohorts were audited to document hospitalization with infection and cross-referenced with the Mayo Clinic infection database, which includes all culture results obtained from hospitalized MCR patients. Serologies and viral assays were also reviewed. Patients whose cultures were negative but who were given a clinical diagnosis of infection (e.g. pneumonia) and who were treated with a full course of antibiotic therapy were considered to have a culture negative infection. RESULTS: In May 2010, there were 2022 CLL patients in the Mayo Clinic CLL Database diagnosed between 1999 and 2009. Of these, 174 (9%) were local CLL patients residing within 50 miles of MCR. Median age at diagnosis for these non-referred CLL patients was 69 years (range 27–97). Most had early stage disease (60% stage 0; 32% stage I-II). On prognostic evaluation, 121 (75%) patients were CD38 negative, 66 (61%) ZAP-70 negative, 47 (50%) IGHV mutated, and 56 (62%) had either no abnormality or 13q14- as a sole abnormality on FISH analysis. 64 (37%) patients progressed to require treatment for CLL during follow-up. After median follow-up of 4.0 years (range 0–11), 32 (18.4%) CLL patients were hospitalized with infection at least once as compared to 20/689 (2.9%) individuals in the control cohort (odds ratio=7.5; p<0.0001) Figure 1A. Even prior to receiving treatment for CLL, the rate of hospitalization for infection remained higher than the control cohort (p=0.002; Figure 1B). The 32 CLL patients hospitalized with infection were admitted with infection a total of 89 times (median 1 hospitalization for infection per patient). A specific infectious organism was identified by cultures or serologies in 60 (63%) of the 89 infections in CLL cases and 10/27 (37%) infections among controls. Hospitalization for an opportunistic infection (e.g. cytomegalovirus, cryptococcus, filamentous fungi, mycobacteria, Pneumocystis) occurred in 5/174 (3%) CLL patients during follow-up compared to 0/689 controls (p<0.001). Finally, we performed a pooled multivariable analysis of all patients (n=863) to identify factors (age, sex, CLL diagnosis, CLL treatment) associated with infection risk. Most factors were independently associated with hospitalization for infection [Age (per year, OR=1.03, p=0.02), sex (male, OR=4.0, p<0.001), diagnosis of CLL (OR=2.1, p=0.09), and treatment for CLL (OR=5.9, p<0.001)]. In univariate analysis of CLL patients [sex (OR=4.2, p=0.01), higher Rai stage (p=0.046), unfavorable (del 17p13; del 11q23) FISH [OR=4.6, p=0.02] and unmutated IGHV [OR=2.8, p=0.07]) were associated with risk of infection. CONCLUSIONS: In this cohort study, patients with newly diagnosed CLL had a 7.5-fold risk of hospitalization for infection relative to the control cohort. After 4 year follow-up, ∼1 in 5 CLL patients required hospitalization for infection. Although CLL treatment was a substantial risk factor for infection, the risk of infection among untreated patients remained higher than controls. Disclosures: Kay: Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity’s Board of Directors or advisory committees. Zent:GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding.