Sharman, Jeff P.

Abstract Introduction CC-292, an oral, highly selective, small-molecule irreversible-inhibitor of Btk is under investigation for the treatment of CLL and other B-cell malignancies. This phase 1 trial investigated the safety, dose limiting toxicities (DLT), and clinical activity of CC-292 monotherapy in subjects with relapsed or refractory (R/R) CLL or non-Hodgkin's lymphoma. This interim analysis focused on the safety and clinical activity in subjects with CLL and small cell lymphocytic leukemia (SLL). Methods Eligible subjects with R/R (≥ 1 prior therapy) CLL/SLL were treated with monotherapy CC-292 in a dose-escalation study with doses ranging from 125 mg to 1000 mg QD and BID dose levels of 375 mg and 500 mg. As a maximum tolerated dose was not established, CLL patients have been enrolled in an early dose expansion cohort of 750 mg QD and preliminary recommended phase 2 dose expansion cohort at 500 mg BID. All subjects received continuous dosing in 28-day cycles until progressive disease or intolerable toxicity. Clinical activity was investigator assessed per the 2008 iwCLL criteria. Results 83 subjects with R/R CLL/SLL have been enrolled as of June 30, 2013. Baseline characteristics include median age of 67 years (34-89), 52% Rai stage 3/4 disease, median 3 prior therapies (1-12), and 34% refractory to last treatment. Poor-risk factors were present in 67% of subjects, including del11q (22%), del17p (24%), and unmutated IgVH (54%). 67% of subjects remain on study. Subjects have received a median of 6 treatment cycles (0.2-21.6). The most frequent grade 3/4 adverse events (AEs) included neutropenia (21%), thrombocytopenia (15%), pneumonia (10%), and anemia (8%). Rates of febrile neutropenia were low (4%). The most common treatment-emergent AEs (≥ 10% of subjects) were diarrhea (59.7%), fatigue (37.5%), neutropenia (26.4%), thrombocytopenia (26.4%), nausea (26.4%), pyrexia (22.2%), headache (19.4%), cough (19.4%), upper respiratory infection (16.7%), peripheral edema (15.3%), abdominal pain (15.3%), dizziness (13.9%), muscle spasms (13.9%), contusion (13.9%), anemia (12.5%), pneumonia (12.5%), sinusitis (12.5%), and urinary tract infection (11.1%). One CLL patient at the 500 mg BID dose level has experienced a drug-related adverse event of grade 4 thrombocytopenia during Cycle 1 that was assessed as a DLT. The number of patients discontinuing study treatment due to AEs was low (2.4%). Results are summarized for efficacy-evaluable patients treated at the 4 dose levels where at least a partial response (PR) was achieved (750 mg, 1000 mg, 375 mg bid and 500 mg bid) (n = 55). During cycle 1, 89% experienced a ≥ 25% increase in absolute lymphocyte count (ALC), which usually resolved with continued treatment. The table below details the best responses achieved to date. In subjects with del11q, del17p, unmutated IgVH, and no high-risk genomic factors, the PR rate was 42% (5/12), 25% (3/12), 44% (7/16), and 47% (7/15), respectively. Importantly, nodal responses were induced in the majority of subjects receiving BID dosing (375 mg: 67%; 500 mg: 62%) with an overall PR rate of 40%. When achieved, nodal responses were typically observed by cycle 2 and were sustained with continued treatment. Although the sample size is small, subjects treated at 375 mg or 500 mg BID showed continued lymph node size reduction over time from cycle 2 (mean reduction of 42% and 45%, respectively) to cycle 7 (mean reduction of 60% and 71%, respectively). Conclusion CC-292 is well tolerated as an oral daily therapy. Single-agent therapy with CC-292 is sufficient to achieve high nodal and partial response rates in relapsed/refractory CLL subjects, including those with high-risk genomic features. These results support continued development of CC-292 for the treatment of patients with CLL/SLL. Disclosures: Brown: Pharmacyclics: Consultancy; Genentech: Consultancy; Celgene: Consultancy, Research Funding; Emergent: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Vertex: Consultancy; Novartis: Consultancy; Genzyme: Research Funding. Off Label Use: The abstract shows scientific information on CC292 which is an investigational product developed by Celgene. This investigational product is not approved by any health authority for any indication. Harb:Celgene: Research Funding. Hill:Celgene: Honoraria, Research Funding. Sharman:Celgene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Cylene Pharmaceuticals: Consultancy, Research Funding; Avila Pharmaceuticals: Consultancy, Research Funding. Barr:Celgene: Consultancy. Foran:Celgene: Research Funding. Burger:Pharmalytics: Research Funding; Gilead: Research Funding. Mahadevan:Novartis: Speakers Bureau; Millennium: Speakers Bureau. Ma:Genentech: Consultancy; Abbvie: Consultancy. Barnett:Celgene: Employment, Equity Ownership. Marine:Celgene: Employment, Equity Ownership. Nava-Parada:Celgene: Employment, Equity Ownership. Azaryan:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Kipps:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction The natural history of patients (pts) with CLL varies considerably. Some pts may have asymptomatic, indolent disease, while others may require therapy soon after diagnosis. Clinical staging systems cannot identify early-stage pts at risk for inferior survival. Genetic and molecular markers can provide additional information regarding prognosis and response prediction, however their utilization is limited in routine practice (Mato, ASCO 2015) and results can be conflicting. There is a need to identify characteristics of early-stage CLL pts at highest risk of early progression and/or death. Such characteristics, if readily available and reproducible, may identify such pts as candidates for early-intervention studies; particularly in the era of kinase inhibitor therapy. The Connect CLL registry is the largest prospective study describing real-world management of a diverse cohort of 1494 CLL pts. In this analysis, we evaluate key factors that are associated with early CLL-associated mortality in clinical practice. Methods Connect CLL is a multicenter, observational cohort study aimed at understanding patterns of CLL management without a study-specific intervention. Eligible pts were adults with a clinical diagnosis of CLL, enrolled between 2010-2014 at 179 community (n=1311), 17 academic (n=155), and 3 government (n=28) sites within ≤ 2 months of initiating either a first line of therapy (LOT1), or a second-line or subsequent LOT (LOT≥2). The goal of this analysis was to assess potential predictors of death occurring within 18 months following initiation of frontline therapy (LOT1). Because CLL usually presents as an indolent disease associated with a prolonged clinical course, we chose to define early mortality as any death occurring ≤ 18 months following enrollment. Univariate logistic regression was performed against potential predictor variables including several clinical characteristics and comorbid conditions, race, treatment (Tx) site, insurance type, geographic region, presence of prior malignancies, genetic prognostic factors (FISH and cytogenetics) at enrollment, cell surface markers (Zap70, CD38), reasons for Tx initiation and Tx choice for LOT1 (BR or FCR). IgVH mutation status and genetic mutations (P53, Notch1, etc.) were not included as these tests were not readily performed in community practice. Predictors that were found to be significant at the 0.15 significance level were included in the multivariable logistic regression using a stepwise variable selection process, to identify factors associated with early mortality. Results 1344 pts completed 18 months of follow-up (n=1111) or died (n=233) within the first 18 months of study enrollment. Of these, 801 pts were enrolled in LOT1 (median time from diagnosis to LOT1 was 1.3 yrs; IQR, 0.1-3.7 yrs). 82 of 801 pts (10.2%) died within 18 months of LOT1 initiation; 41% of pts with available clinical information who died, were defined as early-stage (Rai stage 0-1). Of 26 potential predictors evaluated, 12 were associated with early mortality among LOT1 pts at the 0.15 significance level in univariate analyses including site, race, age>75, CD-38, del(17p), ECOG PS, CCI group, RAI stage, creatinine clearance, insurance status, reasons for Tx initiation, anemia and lymphocytosis. In multivariable logistic regression analyses we identified 4 independent predictors of mortality within 18 months of LOT1 initiation (Table): pt age, CD38 expression, baseline decreased hemoglobin (as a reason for Tx initiation), and race. Conclusions In CLL pts with Rai stage 0-1, we have identified 4 factors which are associated with increased risk of death within 18 months of initiation of frontline therapy. Interestingly, neither choice of FCR vs BR chemoimmunotherapy nor the presence of del(17p)/del(11q) were predictors of early mortality. Using these results, we are currently designing a model to predict early mortality in early-stage pts. Once validated, these results may provide a framework for trials targeting the "early stage, symptomatic" CLL pts for novel interventions. Table. Multivariable Analysis: Predictors of Early Mortality Odds ratio estimate 95% CI P -value LOT1, n=781 Age ≥75 years, yes vs no 2.2 1.4-3.5 0.0012 CD38 expression, positive vs negative/not specified 1.8 1.1-2.9 0.0182 Anemia as reason for treatment, yes vs no 2.1 1.3-3.4 0.0040 Race, other vs Caucasian 1.9 1.0-3.8 0.0501 Disclosures Farber: Gilead: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Mato:TG Therapeutics: Research Funding; Genentech: Consultancy; AbbVie: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Janssen: Consultancy. Nabhan:Celgene Corporation: Honoraria, Research Funding. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Flowers:Spectrum: Research Funding; Pharmacyclics: Research Funding; Infinity Pharmaceuticals: Research Funding; OptumRx: Consultancy; Gilead Sciences: Research Funding; Spectrum: Research Funding; Genentech: Research Funding; Onyx Pharmaceuticals: Research Funding; Acerta: Research Funding; OptumRx: Consultancy; Gilead Sciences: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy; Onyx Pharmaceuticals: Research Funding; Genentech: Research Funding; Millennium/Takeda: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Seattle Genetics: Consultancy; Celegene: Other: Unpaid consultant, Research Funding; Janssen: Research Funding; Millennium/Takeda: Research Funding. Kay:Pharmacyclics: Research Funding; Hospira: Research Funding; Genentech: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharma: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna:Genentech-Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Grinblatt:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Kozloff:Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy. Sullivan:Celgene Corporation: Employment, Equity Ownership. Flick:Celgene Corporation: Employment, Equity Ownership. Kiselev:Celgene Corporation: Consultancy. Bhushan:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene Corporation: Employment, Equity Ownership. Sharman:TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding; Calistoga: Honoraria; Roche: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding.

Abstract Introduction: Results of several large clinical trials have demonstrated inferior outcomes when CLL patients (pts) with del(17p), or to a lesser extent del(11q), are treated with chemoimmunotherapy. Despite recent advances in targeted therapies, management of unfavorable-risk CLL pts remains challenging. The Connect CLL registry is the largest prospective study describing real-world management of a diverse cohort of CLL pts. Here we describe the management of genetically unfavorable-risk CLL pts enrolled in the Connect CLL Registry, and test associations between del(17p)/del(11q) mutations and treatment choice, timing of therapy, and outcomes. Methods: Connect CLL is a longitudinal, multicenter, observational cohort study of 1,494 CLL pts enrolled between 2010-2014 at 179 community (n=1,311), 17 academic (n=155), and 3 government (n=28) sites within ≤ 2 months of initiating any line of therapy (LOT). For this study, pts were categorized into 3 risk-groups based on FISH or cytogenetic results at enrollment: unfavorable risk [either del(17p)/del(11q) positive]; favorable risk [absence of del(17p)/del(11q)]; and unknown risk (testing not performed). Analyses were stratified by LOT at enrollment (LOT1 vs LOT≥2). The risk of an EFS defining event was compared across risk-groups stratified by LOT, including only pts who had been followed for ≥ 2 years (yr) or those who had an EFS defining event (death, progression/relapse, transformation) within 2 yr, using multivariable (MV) logistic regression. Logistic regression analyses of 18 potential predictors were performed, and significant predictors (0.10 significance level) were then included in a MV logistic regression model to identify factors associated with inferior 2 yr EFS. Results: Of 1,494 pts enrolled, 225 had unfavorable risk [del(17p), n = 94; del(11q), n = 131], 621 favorable risk, and 648 unknown risk. For pts enrolled at LOT1 (n = 889), 141 had unfavorable risk, 425 favorable risk, and 323 unknown risk. Baseline characteristics for unfavorable-risk pts in LOT1 included: median age 69 yr (62% age ≥ 65 yr); 91% White; 53% Rai stage ≥ 2; 86% community sites; 0.9 yr median time from dx to LOT1; 8% family history CLL. With the exception of age, unfavorable-risk pts treated at LOT1 with FCR (median age 63) and BR (median age 74) had similar demographic characteristics. Median time from dx to LOT1 was 1.0, 1.3, and 2.0 yr for unfavorable risk, favorable, and unknown-risk pts, respectively (P < 0.001 for comparison of the 3 risk-subgroups). Reasons for initiating treatment in unfavorable-risk pts were lymphadenopathy (42%), bone marrow failure (36%), and lymphocytosis (33%) (similar across the 3 risk-subgroups). The three most common therapies for unfavorable-risk pts in LOT1 were FCR (36%), BR (21%), and FR (6%). Favorable-risk (FCR 26%, BR 24%, and R 10%) and unknown-risk pts (FCR 22%, BR 18%, and R 17%) were treated similarly in LOT1. Median time from dx to LOT≥2 was 3.5 yr in unfavorable-risk pts (vs 4.1 yr in favorable and 4.6 yr in unknown risk pts; P = 0.04 for comparison of the 3 risk-groups). For unfavorable-risk pts in LOT≥2, BR (26%), R (11%), and FCR (10%) were most commonly prescribed. At any LOT, only 10% of unfavorable-risk pts participated in a clinical trial and 4% underwent allogeneic SCT. Overall, 33% (LOT1) and 68% (LOT≥2) of pts experienced an EFS defining event within 2 yrs. Pts with unfavorable risk (vs favorable risk) had significantly worse outcomes, with a higher-risk of death/progression/relapse/transformation within 2 yr (LOT1: 42% vs 29%, respectively, P = 0.008; and LOT≥2: 80% vs 61%, P = 0.004). Unfavorable-risk pts treated with either FCR or BR at LOT1 had similar risk of an EFS defining event (odds ratio [OR] 0.9, CI 0.6-1.5). Results from MV analyses of LOT1 pts identified unfavorable risk (OR 1.9; 95% CI 1.1-3.1; P = 0.0168) and age ≥ 75 years (OR 2.6; 95% CI 1.5-4.3; P = 0.007) as independent predictors of inferior EFS at 2 yr. Conclusions: Although similar treatment approaches were used among the 3 risk-subgroups, pts with unfavorable-risk CLL had inferior outcomes at LOT1 and LOT≥2. These results, from a real-world setting, validate the findings for unfavorable risk pts from large clinical trials. These data underscore the importance of performing genetic risk stratification on all CLL pts, and support consideration of clinical trials and/or B cell receptor targeted agents for unfavorable risk CLL pts when treatment is considered. Disclosures Mato: Janssen: Consultancy; AbbVie: Consultancy, Research Funding; Genentech: Consultancy; Pronai Pharmaceuticals: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding. Nabhan:Celgene Corporation: Honoraria, Research Funding. Flowers:Celegene: Other: Unpaid consultant, Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Spectrum: Research Funding; Infinity Pharmaceuticals: Research Funding; OptumRx: Consultancy; Onyx Pharmaceuticals: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; Seattle Genetics: Consultancy; Onyx Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Millennium/Takeda: Research Funding; Infinity Pharmaceuticals: Research Funding; Spectrum: Research Funding; Millennium/Takeda: Research Funding; Pharmacyclics: Research Funding; OptumRx: Consultancy; Gilead Sciences: Research Funding; AbbVie: Research Funding; Seattle Genetics: Consultancy; Acerta: Research Funding. Kay:Pharmacyclics: Research Funding; Genentech: Research Funding; Tolero Pharma: Research Funding; Celgene Corporation: 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. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor; Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Grinblatt:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Lamanna:Genentech-Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kozloff:Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy. Sullivan:Celgene Corporation: Employment, Equity Ownership. Flick:Celgene Corporation: Employment, Equity Ownership. Kiselev:Celgene Corporation: Consultancy. Bhushan:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene Corporation: Employment, Equity Ownership. Sharman:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Calistoga: Honoraria; Roche: Research Funding; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Research Funding.

Key Points Early progression of disease within 2 years of initial therapy independently predicts inferior survival in CLL. Early progression of disease is a robust clinical end point and a useful posttreatment risk stratification tool.

Abstract The majority of pts with newly diagnosed CLL are classified with Rai stage 0 or 1 disease and typically experience an indolent clinical course. However, little is known regarding the reasons for initiating therapy in this population or patterns of initial treatment in the contemporary era of our practicing community. We utilized data from the Connect CLL registry, a US-based multi-center, prospective observational cohort study that is aimed at understanding patterns of CLL management without a study-specific intervention. Eligible pts were adults with a clinical diagnosis of CLL who initiated therapy ≤2 months prior to enrollment, and were enrolled from academic (n=155), community (n=1311), or government (n=28) sites between 2010-2014. Descriptive statistics were applied to examine data on demographics, baseline characteristics, treatment selection, early treatment outcomes, and reasons for initiating therapy that were reported for pts with Rai 0/1 CLL receiving first-line therapy. Multivariable logistic regression models were constructed to evaluate predictors of complete response (CR) and event-free survival (EFS) defined as the occurrence of the first of disease progression, relapse or death within 24 months of enrollment. Among 684 pts who received first-line therapy at enrollment and for whom Rai stage was available, 363 had Rai 0/1 CLL. This group had a median age of 68 years (range 41-90); 94% were white, 60% male, 98% insured, and 93% were treated in community practices; 47% had Rai stage 0 disease (54% Binet A); 33% had ≥1 constitutional symptoms; 96% had ECOG performance status of 0 or 1; 35% had conventional cytogenetics and 53% had FISH analysis performed. Among pts for whom cytogenetic or FISH analysis were performed, 159 (72%) were abnormal, of them 37 pts (23%) had del(11q), 104 pts (65%) had del(13q), 33 pts (21%) had trisomy 12, and 20 pts (13%) had del(17p) by conventional cytogenetics and/or FISH, including 8% with del(17p) by FISH. The median time from diagnosis to initiation of therapy was 2.5 years (range 0-20 years) for Rai 0/1 pts compared with 0.5 years for pts enrolled with Rai stage ≥2 (range 0-32). The most common reasons for initiating therapy (with >1 reason possible) in Rai 0/1 CLL were: bulky or progressive or lymphadenopathy (40%), progressive lymphocytosis (39%), any disease-related symptom (weight loss, fatigue, fever, night sweats; 28%), anemia (20%), and thrombocytopenia (15%); 42% of pts had >1 reason for initiation. The most common first-line regimens used in this cohort were: fludarabine/cyclophosphamide/rituximab (FCR; 29%), bendamustine/rituximab (BR; 20%), and rituximab alone (12%). Of the 317 pts who either responded to treatment during the first 24 months of enrollment or were followed ≥24 months, 143 pts (45%) achieved CR (investigator assessed as per protocol) and 264 (83%) achieved CR or partial response. Female gender (odds ratio [OR] = 2.22), treatment with BR or FCR (OR = 3.41), and time from diagnosis to therapy (OR = 0.92; with each year increase in time from diagnosis to initiation of therapy, relative odds of CR decreases by 8%), were independent predictors of CR. Of the 311 evaluable pts, 82 pts (26%) experienced an EFS event during the 24 months on study, of which 19 (23%) were deaths and 48 (59%) were progressions. Age ≥75 years (OR = 4.46), lymphocytosis as a reason for therapy initiation (OR = 1.89), and male gender (OR = 1.73) were independent predictors of an EFS event within 24 months. The Connect CLL registry represents the largest comprehensive prospective cohort of CLL pts collected from multiple practices across the US. In concordance with other studies, pts with Rai 0/1 initiated therapy approximately 2.5 years following CLL diagnosis and included a cohort of pts with poor prognostic FISH characteristics. Although chemoimmunotherapy was associated with a significantly higher likelihood of CR, progressive lymphocytosis as a reason for initiating therapy (and not any form of treatment) was more likely to predict an early EFS event. Approaches using novel agents or combination therapies aimed towards addressing pts with progressive lymphocytosis should be considered in future studies. Disclosures Flowers: Seattle Genetics: Consultancy; OptumRx: Consultancy; AbbVie: Research Funding; Pharmacyclics: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Spectrum: Research Funding; Onyx Pharmaceuticals: Research Funding; Spectrum: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Research Funding; Janssen: Research Funding; Millennium/Takeda: Research Funding; Onyx Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Millennium/Takeda: Research Funding. Nabhan:Celgene Corporation: Honoraria, Research Funding. Kay:Pharmacyclics: Research Funding; Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharma: Research Funding. Mato:AbbVie: Consultancy, Research Funding; Janssen: Consultancy; Celgene Corporation: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy. Lamanna:Genentech-Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Grinblatt:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor; Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Kozloff:Roche: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; AbbVie: Consultancy. Sullivan:Celgene Corporation: Employment, Equity Ownership. Flick:Celgene Corporation: Employment, Equity Ownership. Kiselev:Celgene Corporation: Consultancy. Bhushan:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene Corporation: Employment, Equity Ownership. Sharman:TG Therapeutics, Inc.: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding; Calistoga: Honoraria; Celgene Corporation: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Roche: Research Funding.

Abstract Abstract 3926 Introduction. Chronic lymphocytic leukemia (CLL) patients will have significant variation in signs and symptoms at initial presentation and across lines of therapy, with concomitant effect on patient health-related quality of life (HRQOL). HRQOL and other patient-reported outcomes, together with clinical outcomes, provide a more complete perspective on the burden of disease and facilitate a broader view of the impact of treatment regimens. This analysis evaluates whether the HRQOL of patients with CLL in the United States (US) varies at the time the patients are about to embark on various lines of therapy, and offers a baseline report from which subsequent longitudinal analysis post-treatment will be possible. Methods. Clinical and HRQOL data were collected in Connect®CLL, a prospective observational registry initiated in March 2010 involving centers in the US. Physicians provided data on the demographics and clinical characteristics of patients receiving therapy. HRQOL was self-reported by patients at enrollment using the Brief Fatigue Inventory (BFI, a symptom assessment tool), the EQ-5D (a non-disease-specific HRQOL instrument), and the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu, a leukemia-specific HRQOL instrument). We characterized patients who had initial (First Line), second (Second Line) or subsequent (Higher Line) treatment regimens prior to initiation of regimens. Reported mean overall and/or domain-specific BFI, EQ-5D and FACT-Leu scores were analyzed by line of therapy. Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results. Evaluable data were reported on 1005 patients, enrolled from 161 centers (93% community, 7% academic). Patients were predominantly male (62%) and white (89%) with mean age at 69 (standard deviation [SD] 11) years. HRQOL scores by line of therapy are presented: The total FACT-Leu and FACT-G results, and the total EQ-5D Index and Visual Analogue Scale (VAS) results, consistently suggest that patients initiating first line therapy have somewhat better HRQOL compared with those initiating subsequent lines of therapy. FACT-Leu total scores of patients initiating first line therapy were associated with better physical and leukemia-specific considerations, and the EQ-5D total score was associated with better mobility and pain/discomfort. Conclusions. Initial results from the Connect® CLL Registry indicate that HRQOL prior to treatment is better among patients initiating first line therapy compared to patients initiating later lines of treatment. Future analyses should be conducted to determine what clinical or other factors may be associated with the HRQOL deterioration in patients initiating subsequent lines of therapy, so as to inform clinician decision making. Also, subsequent longitudinal analyses should be undertaken to determine how HRQOL might be affected by the different lines of therapy and the specific treatment regimens, as well as by their initial HRQOL and other patient factors. Disclosures: Kay: Celgene: Research Funding. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Research Funding, Unpaid consultancy, Unpaid consultancy Other; Genentech: Unpaid consultancy, Unpaid consultancy Other; Gilead: Research Funding; Spectrum: Research Funding; Janssen lymphoma research foundation: Membership on an entity's Board of Directors or advisory committees. Weiss:Celgene: Consultancy. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Celgene: Research Funding. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kipps:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kozloff:Celgene: Consultancy. Lerner:Celgene Connect: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Consultancy; Pharmacyclics: Honoraria; Calistoga: Honoraria; Portola pharmaceuticals: Consultancy. Khan:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Swern:Celgene: Employment. Sullivan:Celgene: Employment. Pashos:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

SummaryThe clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real‐world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community‐, 17 academic‐, and 3 government‐based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient‐level observational data that represent real‐world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice.

AbstractCertain malignant B cells rely on B-cell receptor (BCR)–mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered at www.clinicaltrials.gov as #NCT00446095.