Bowen, Deborah A.

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.

Abstract BACKGROUND: Studies have suggested that patients with CLL are at a significantly increased risk of developing other lymphoid malignancies. Whether the risk of developing a 2nd lymphoproliferative disorder (LPD) is more strongly related to characteristics of the leukemia cell or to other factors such as prior chemotherapy is unknown. This distinction is important given increasing momentum to pursue early treatment of CLL patients based on recently identified prognostic markers, e.g. ZAP-70, IgVH mutation status. We used the Mayo Clinic CLL Database (DB) to conduct an observational cohort study to evaluate the relationship between clinical, biologic, and treatment characteristics and the risk of secondary LPD. METHODS: The Mayo Clinic CLL DB was established in 1999 and included 962 patients at the time of the present analysis. Clinical information regarding date of diagnosis, prognostic parameters, treatment history, disease-related complications, and co-morbidities was abstracted from clinical records on all patients at the time of study enrollment and maintained on an ongoing basis. For the present study, cases of secondary LPD were identified by chart review and cross referencing patient clinic numbers from the CLL DB with the Mayo Clinic Lymphoma and Leukemia/Myelodysplasia databases. Additionally, all clinic numbers were cross-referenced with an electronic hematopathology database that has recorded results of all bone marrow and lymph node biopsies of all Mayo Clinic patients since 1992. RESULTS: A second LPD was identified in 26 (2.7%) of the 962 CLL patients during a median follow-up of 7.12 years (range 0.1–21.0). The median time from diagnosis to development of secondary LPD was 4.4 years (range 0–19 years). Diffuse large B-cell lymphoma was the most common subtype of secondary LPD (12 of 26 cases). Gender was associated with increased risk of developing 2nd hematologic cancer where 1% of women compared to 3.4% of men (p=0.051) developed a 2nd LPD. Treatment history was also related to development of a 2nd LPD. 2nd LPD developed among 4% of previously treated CLL patients compared to 2% of untreated patients (p=0.08). Among the 362 patients who were treated for CLL prior to developing a second LPD, the median time to first treatment was shorter for those who developed a 2nd LPD (2.43 years vs. 6.22 years; p<0.001). No statistically significant association was observed between other clinical or biologic leukemia cell characteristics and development of 2nd LPD including IgVH gene mutation status, ZAP-70 status, CD38 status, cytogenetic abnormalities by FISH, B2M, stage at diagnosis, or ALC at diagnosis. CONCLUSIONS: In this observational cohort study, prior treatment demonstrated a stronger correlation with the risk of developing a 2nd LPD than did leukemia cell characteristics including IgVH gene mutation status, FISH, ZAP-70, B2M, and CD38. This finding suggests Richter’s transformation may relate more to therapy than characteristics of the leukemia cell itself. Until the results of clinical trials evaluating the role of early treatment based on prognostic parameters are available, this result underscores the importance of delaying administration of chemotherapy until patients meet established criteria for treatment.

Abstract Background: CLL patients (pts) treated with novel targeted therapies continue to experience disease progression. Approximately 7-15% of relapsed CLL treated with ibrutinib or venetoclax developed Richter's syndrome (RS), an aggressive high grade lymphoma transformation. Standard chemotherapy has limited efficacy in RS. We hypothesized that checkpoint blockade would re-establish anti-tumor immune response in progressive CLL/RS and here we aim to update the clinical data and correlative analysis of MC1485: a phase 2 study of PD-1 blocking antibody pembrolizumab in relapsed/refractory CLL and RS. Methods: Relapsed/refractory CLL including RS enrolled in the CLL arm of MC1485 trial was reported here. The primary end point of this study is overall response rate (ORR). Pts with prior allogeneic stem cell transplant were excluded. Pembrolizumab 200 mg was administered intravenously every 3 weeks. NCI CTCAE v4.0 and IWCLL 2008 criteria were used for non-hematological adverse events (AE) and for CLL grade hematological AE. Tumor expression of PD-1 and PD-L1 were assessed with standard immunohistochemical (IHC) staining. Percentage expressions of individual antigens were analyzed with whole-slide scanning followed by image analysis with Image-Pro software (Media Cybernetics). Fluorescence in situ hybridization (FISH) was performed on available CLL/RS tissue sections to assess copy number of chromosome 9p region that contains PD-L1 and PD-L2. Results: 25 pts including 16 CLL and 9 RS (biopsy-proven large cell lymphoma) were enrolled in CLL arm. The median age was 69 years (46-81). Twelve (48%) pts had del(17p) or monosomy 17 or TP53 mutation. The median number of prior therapies was 4 (1-10). 96%, 72% or 48% of pts had received alkylator and anti-CD20 antibody, purine analog or anthracycline. Fifteen (60%) pts had prior ibrutinib and 12 (48%) progressed clinically while receiving ibrutinib, including 6 who progressed to RS and 6 who developed progressive CLL. The median number of pembrolizumab doses that pts received was 3 (1 to 21), administered over a median treatment duration of 11 weeks (1 to 56). Drug-related AE occurred in 21 pts (88%) with the most common ones being neutropenia in 9 (37%), cough in 7 (29%) and dyspnea in 6 (25%) pts. Drug-related grade 3 or above AE occurred in 9 (38%) pts with most common ones being thrombocytopenia (5, 21%), dyspnea (2, 8%), and fatigue (2, 8%). The most common immune-related AE was liver enzyme elevation (12%, 8% G3) and was reversible with therapy interruption or steroid therapy. Based on investigator assessment using the Revised Response Criteria for Lymphomas and IWCLL 2008 criteria, one RS pt had complete response (CR, 4%), 3 RS had partial responses (PR, 12%). Among 9 RS pts, 1 CR (11%), 3 PR (33%), 3 SD (33%) and 2 PD (22%) were observed. Thus the ORR in RS was 44%. No CLL pts achieved a CR/PR, 3 had SD and 9 had progressive disease (PD). The ORR of all pts was 16%. Of the 4 RS who had CR/PR, responses occurred early after 2 cycles of therapy and median duration of therapy for CR/PR pts was 8.3 months with data cut-off by June 30th 2016 (Figure 1A). The causes for therapy discontinuation in RS were PD (3, 33%), alternate therapy (2, 22%), and thrombocytopenia due to increased marrow CLL (1, 11%). Increased marrow CLL was observed in 2 RS pts with PR to RS phase of disease assessed by PET, thus the protocol was amended to allow addition of idelalisib/ibrutinib to control the underlying marrow CLL. For RS pts who had a CR/PR or SD, variable nodal responses were observed (Figure 1B). In particular, 6 RS who had prior ibrutinib experienced CR or PR or SD with nodal responses. After a median follow-up of 10.2 (1.9 to 16.1) months, the median overall survival (OS) for all pts was 10.7 months (95% confidence interval [CI], 5.4 to not reached). The 6 month OS rate for RS and CLL pts were 73% and 59%, respectively. Biomarker assessment using IHC analysis on 10 pts with available tumor/nodal tissues (6 RS and 4 CLL) showed an increased expression of PD-L1 (p = 0.02) and a trend for an increased expression of PD-1 (p = 0.1) in the group of pts with CR/ PR versus pts in the group with no clinical response. One out of 10 tested showed polysomic for chromosome 9p. Conclusion: Pembrolizumab had an acceptable safety profile in CLL and RS patients. We confirmed that pembrolizumab has substantial therapeutic activity in RS. Single-agent pembrolizumab does not appear to have clear activity in CLL. Disclosures Ding: Merck: Research Funding. Parikh:Pharmacyclics: Honoraria, Research Funding. Shanafelt:GlaxoSmithKline: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Hospira: Research Funding.

Abstract Abstract 1792 High risk disease can be identified in patients with early stage chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) using biological prognostic markers. We have shown that early therapy of high risk CLL patients with alemtuzumab (ALM) and rituximab (RTX) is effective and could possibly delay first standard treatment (Cancer 2008;113:2110-8). Efficacy of unconjugated monoclonal antibody (mAb) therapy in these patients could be improved by enhancing mAb mediated cellular cytotoxicity. Preclinical studies show that yeast cell wall derived beta glucan, which increases complement receptor 3 (CR3) binding to the complement fragment iC3b on target cells, could increase mAb mediated cellular cytotoxicity. Both ALM and RTX activate complement resulting in deposition of iC3b on the cell membrane. In CLL cells that are not lysed by complement activation, these iC3b molecules are targets for the effector cells mediating cellular cytotoxicity. We hypothesized that PGG beta glucan (Imprime PPG®, Biothera, Eagan MN) an intravenous formulation of a 1,3/1,6 glucose polymer prepared from a strain of Saccharomyces cerevisiae, would improve the efficacy of therapy with ALM and RTX in patients with CLL by increasing CR3 binding to iC3b and thus enhancing macrophage, neutrophil, and NK cell mediated cytotoxicity. We report the results of a Phase I study of the combination of ALM, RTX and PPG beta glucan in patients with CLL. Methods: The primary aim of this IRB approved study (NCT01269385) was to determine the maximum tolerated dose (MTD) of PGG beta glucan that could be safely combined with ALM and RTX. The MTD was defined as the PGG beta glucan dose level below that which induced dose limiting toxicity in at least one third of patients, or the highest dose level tested if all levels were tolerated. Eligibility for the trial required a diagnosis of CLL by standard (IWCLL-NCI 2008) criteria, no prior treatment for CLL, high risk CLL based on molecular markers, absence of standard indications for initiation of therapy for CLL, and adequate performance status and organ function. High risk CLL was defined as at least one of the following: 17p13-; 11q22-; either unmutated (<2%) IGHV or use of VH3–21 as well as CD38+ and/or ZAP70+. Patients received standard premedication for mAb, antimicrobial and allopurinol prophylaxis and weekly PCR testing for CMV reactivation with treatment of viremia. The duration of treatment was 33 days. PGG beta glucan was administered IV on days 1, 5, 10, 17, 24, and 31 and the first dose was premedicated with hydrocortisone 100mg IV, oral acetaminophen 1000 mg and diphenhydramine 50 mg. The starting dose level of PGG beta glucan was 1 mg/kg, 2nd dose level was 2 mg/kg and the 3rd dose level 4 mg/kg. Subcutaneous ALM therapy started on day 3 with daily dose escalation (3 – 10 – 30 mg) and then 30 mg Mon-Wed-Friday for 4 weeks. Weekly RTX started on day 10 at 375 mg/m2 IV × 4 doses. Results: Thirteen patients were enrolled from February 2011 to April 2012. The 11 evaluable patients had a median age of 61 years (range 47 – 77), 73% were male, 3 had early stage disease (Rai 0) and 8 had intermediate stage disease (Rai I n = 7, Rai II n = 1). High-risk parameters were 17p- in 4 patients, 11q22- in 3 patients, and unmutated IGHV and expression of ZAP70 and/or CD38 in 4 patients. There were no dose limiting toxicities. One patient had grade 4 febrile neutropenia, with no grade 3–4 anemias or thrombocytopenias, and there were no grade 3–4 non-hematological toxicities. All patients responded to therapy with 7 CR, 1 CCR, 1 nPR, and 2 PR (IWCLL-NCI 2008 criteria). Median follow up was 6.9 months (2.3 – 13.2) and one patient progressed at 9.7 months. No patients have required treatment for progressive disease and there have been no patient deaths. Two patients were not evaluable: One developed neutropenia and therapy was not held per protocol, and the other developed a grade 2 skin reaction to ALM and treatment was stopped. Discussion: The combination of PGG beta glucan with ALM and RTX is well tolerated at a PGG beta glucan dose of 4 mg/kg. All patients responded to therapy with 64% achieving a CR. These data support continuation of this study in a phase II component. Acknowledgment: This study was funded by the University of Iowa/Mayo Clinic Lymphoma SPORE (CA097274) and Biothera. Disclosures: Zent: Biothera: Research Funding; Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding. Off Label Use: Phase I study using PGG beta glucan in CLL.

Abstract Background: Individuals with clinically ascertained monoclonal B-cell lymphocytosis (c-MBL) having the phenotype of the chronic lymphocytic leukemia (CLL) have a 1-4% per year risk of progression to CLL requiring therapy. The risk factors for progression and the outcomes of individuals with c-MBL are not well defined. Methods: Using the Mayo Clinic CLL Database, we identified individuals with c-MBL (absolute B-cell count of <5x109/L, in the absence of symptoms, organomegaly, splenomegaly and cytopenias) who were seen at Mayo Clinic, Rochester, MN between 01/1995 - 5/2016. Patients in whom an absolute B-cell count was not available were included in the analysis if the absolute lymphocyte count was <5x109/L. Baseline clinical characteristics and prognostic test results (including IGHV mutation status, genetic abnormalities detected by FISH, and expression of ZAP-70, CD38 and CD49d) were recorded. Time to first therapy (TFT) was analyzed using cumulative incidence methods accounting for competing risk of death. Multivariable Cox proportional hazards regression analysis was used to identify factors that predicted TFT. Because of missing data for some prognostic parameters, multiple models were run, introducing one novel prognostic factor at a time to the base model (which consisted of age and sex). Overall survival (OS) of these individuals was compared to age- and sex-matched population of the state of Minnesota. Results: Eight hundred and fifty-one individuals with c-MBL were identified and included in this analysis. Median age was 69 years (range, 38-95 years), and 527 (62%) were males. The median absolute B-cell count at the time of diagnosis was 2.6 x 109/L (range, 0.1-5.0 x 109/L). The median serum beta-2 microglobulin (β2M) was 2.2 mg/dL (range, 1.0 - 21.5 mg/dL). One hundred and nine (30%) individuals had unmutated IGHV genes, and 38 (7%) had high-risk FISH (defined as either del17p13 or del11q23). The CD38 (≥30%), ZAP-70 (≥20%), and CD49d (≥30%) status was positive in 19%, 23% and 34% individuals, respectively. After a median follow-up of 6.8 years, 99 individuals required therapy for progressive disease (at a rate of 2.1% per year, Figure 1). On multivariable analysis, the following factors were associated with a higher risk of progression to CLL requiring therapy: a) unmutated IGHV status (hazard ratio [HR]:3.8, 95%CI 2.1 - 7.0, p<0.0001); b) positive CD49d status (HR: 3.1, 95%CI 1.6 - 5.9, p=0.0006); and c) positive CD38 status (HR: 2.8, 95% CI 1.7 - 4.8, p<0.0001). Although the HR for high-risk FISH was 2.0 (95% CI 0.9 - 4.4), it was not significantly associated with TFT (p=0.11), likely due to small sample size. Age, sex, serum β2M, and ZAP-70 expression were not predictive of TFT. Among these individuals with B-cell counts <5x109/L, further stratification of the absolute B-cell count at diagnosis showed no association with TFT (Figure 2). The median OS of individuals with c-MBL was 11.8 years. Although the OS among individuals with c-MBL and the age- and sex-matched general population of Minnesota appeared similar for the first 10 years of follow-up, OS was significantly shorter in the c-MBL group during the full follow-up interval (p=0.004, Figure 3). Conclusion: In this large cohort of individuals with clinically ascertained MBL, the risk of progression to CLL requiring therapy was 2.1% per year. Biological characteristics of the B-cell clone including IGHV mutation status, and CD49d and CD38 status predicted time to first CLL therapy. On extended follow-up, the OS of individuals with c-MBL was significantly shorter relative to age- and sex-matched general population. These findings have important implications for counselling individuals with clinically ascertained MBL. Disclosures Parikh: Pharmacyclics: Honoraria, Research Funding. Ding:Merck: Research Funding. Kenderian:Novartis: Patents & Royalties, Research Funding. Shanafelt:Pharmacyclics: Research Funding; GlaxoSmithkKine: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Hospira: Research Funding.

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: Historically, CLL patients with cytopenia were thought to have a poor prognosis and cytopenia is a key feature of CLL clinical staging systems. The implications of cytopenia in CLL could have changed because of improved diagnostic accuracy, increased recognition of early stage disease, and better treatments. Newer data suggest that the etiology of cytopenia determines its prognostic importance in CLL. Patients with cytopenia caused by autoimmune disease (AID) are less likely to have the poor prognosis associated with patients with bone marrow (BM) failure. To determine the prognostic significance of cytopenia in patients with CLL, we performed an observational study at Mayo Clinic Rochester (MCR). Methods: We studied all patients with CLL seen in the Division of Hematology at MCR from 1 January 1995 to 31 December 2004 (n = 1,750). Cytopenia (hemoglobin < 10 g/dL or platelet count < 100 × 09/L) was considered due to BM failure in patients with extensive BM involvement by CLL (< 20% residual myeloid tissue on BM biopsy) or reticulocytopenia without other causes persisting > 3 months after CLL therapy. Cytopenia was attributed to AID in patients with autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), pure red blood cell aplasia (PRCA), or autoimmune granulocytopenia (AIG). Results: Median age at diagnosis of CLL was 63.7 years (69% male). Cytopenia occured in 423 (24.2%) patients. In 303 patients, cytopenia was due to CLL (228 BM failure and 75 AID). In 120 patients cytopenia was due to CLL related factors (splenomegaly, n = 11; possible AID, n = 18; treatment of CLL, n = 16) or non CLL causes (other malignancy, n = 12; iron deficiency, n = 11; anemia of chronic disease, n = 10; renal failure, n = 6; drugs effect, n = 4; surgical blood loss n = 4). In 28 (6.6%) patients the cause of cytopenia was not definitively determined. Of the patients with BM failure, 97 (43%) had cytopenia at CLL diagnosis (70% male, median age 63.3 years [range 32–95]), The AID patients the median age of CLL diagnosis was 66.7 years (range 30–85) with 79% male. AID diagnoses were AIHA (n = 41), ITP (n= 35), PRCA (n=8), and AIG (n=3); 9 patients had > 1 AID. Survival from diagnosis of cytopenia was significantly better for patients with AID (median 9.1 years) than BM failure (median 4.4 years, p < 0.001). AID patients had a longer survival from diagnosis of CLL (median 12.4 years) versus the rest of the CLL population (median 9.5 years, p = 0.020) but patients with BM failure at diagnosis had a worse prognosis (median 6.2 years, p < 0.001). Conclusion: We show that the etiology of cytopenia in CLL patients determines its prognostic importance. Anemia and thrombocytopenia caused by BM failure, but not AID, are associated with a significantly worse prognosis. These data show the importance of accurate determination of the etiology of cytopenia in all patients with CLL. Cytopenia in patients with AID is not a marker of advanced stage disease; these patients often need different management compared to those with BM failure. Cytopenia due to AID versus BM failure can be difficult to distinguish and a BM study should be done in all patients considered for treatment. Patients with cytopenia due to AID cannot be meaningfully classified by current clinical staging systems. We believe that efforts to review the NCI-WG 96 criteria are timely and should consider the etiology of cytopenia in CLL patients.

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.