Flowers, Christopher R.

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 3708 Background: There are few prospective studies on disease characteristics, patterns of care, response, and outcomes in elderly FL patients (pts) in the US. The NLCS is a Genentech-sponsored prospective multicenter registry study that collects this information without study-specific treatment. We utilized the NLCS database to better understand the impact of age on FL outcome. Patients and Methods: All evaluable pts with FL histology in the NLCS were included except pts with FL plus other lymphoma histology or pts who progressed before first treatment or before being assigned to watchful waiting (WW). Using Pearson Chi-Square tests, associations of age groups (≤60, 61–70, >70) with disease characteristics and overall response (ORR) were examined. Median PFS and OS by treatment regimen were estimated using Kaplan-Meier methods for each age group. Cox proportional hazards regression adjusted for baseline factors (grade, number of nodal sites, LDH, Hgb, stage, performance status (PS), bone marrow (BM) involvement, race, and treatment center type) were used to assess treatment differences in PFS and OS and the significance of age by treatment interactions. Results: Of 2,647 pts, 47% (n=1,254) were ≤60 yrs, 25% (n=666) were 61–70 yrs, and 27% (n=727) were >70 yrs (min age of 22; max of 97). Compared with pts ≤60 yrs, pts 61–70 and >70 were more likely to be white (93% >70, 92% 61–70, and 88% ≤60, P=.02 and .02 respectively), have stage I/II disease (37% >70, 36% 61–70, and 29% ≤60, P=.0008 and .0003), have <5 nodal sites (73% >70, 69% 61–70, and 61% ≤60, P=.001 and <.0001), and have poor-risk FLIPI (53% >70, 51% 61–70, and 15% ≤60, P<.0001 and <.0001). Compared with pts ≤60, elderly pts (>70) were more likely to have FL grade 3 (24% vs 18%, P=.01). While there were no differences in geographic distribution by age, elderly pts were more likely to receive therapy at community practices (86%) versus academic institutions than pts ≤60 (77%, P<.0001) or 61–70 (81%, P=.004). Treatments varied significantly by age (P<.0001). More elderly pts were observed compared to pts ≤60 (23% vs19%). When treated, elderly pts (22%) were more likely to receive rituximab (R) monotherapy compared with patients aged 61–70 (12%) or ≤60 (10%). When chemotherapy alone or plus R was given, elderly pts were less likely to receive anthracyclines (45% vs 65% (61–70) and 68% (≤60)). Among all variables, only grade 3 histology predicted anthracycline use in all age groups. Lack of BM involvement predicted anthracycline use for younger pts (≤60 and 61–70). Of those ≤60, white pts were more likely to receive anthracyclines, and of those 61–70, those with ≥5 nodal sites were more likely to receive anthracyclines. ORRs were similar across age groups receiving similar regimens with R plus chemo providing the highest ORR. Adjusting for baseline factors, treatment (WW, R, R-Chemo, or other) benefit varied for each age group in terms of PFS (P=.02), with treatment outcomes being most differentiated among younger pts (Table). PFS appeared shorter in elderly pts regardless of the treatment received. No significant interaction between age and efficacy of anthracycline in terms of PFS or OS was observed (P-values >.65), but the overall effect of anthracycline for all pts was beneficial for PFS (HR=0.80, P=.02) and OS (HR=0.67, P=.003). Median OS was 8 years for elderly and not reached for others. After adjusting for baseline factors, no significant differences in treatment impact by age on OS were seen. Elevated LDH, reduced Hgb, stage III/IV, PS ≥1, and BM involvement were all significantly associated with shortened OS. These factors were also significantly associated with treatment choice, as worse-prognosis elderly pts were more likely to receive either R or R+chemo than WW or other treatment. Conclusions: FL pts >70 yrs more commonly received R alone and less commonly received anthracyclines when treated with chemotherapy. The impact of anthracyclines on PFS did not vary by age, but differences in PFS for other treatment regimens showed a stronger association among younger pts Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau. Byrtek:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Dawson:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Link:Genentech, Inc., a member of the Riche Group: Consultancy; Celgene: Consultancy; Spectrum: Consultancy. Friedberg:Genentech: Consultancy. Cerhan:Genentech: National LymphoCare Scientific Advisory Board Other. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy, Research Funding; Genentech: Consultancy; GIlead: Research Funding; Spectrum: Research Funding; Janssen: Research Funding; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees.

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.

Abstract Abstract 3702 Background: Both drug choice and delivered dose of intended treatment potentially influence outcome in patients treated for follicular lymphoma (FL). Historically, observational studies have solely evaluated drug choice. The National LymphoCare Study (NLCS) is a prospective, observational study that enrolled >2700 patients with FL in the United States between 2004 and 2007. We report on measures of delivered dose and its impact on outcomes for the most common first-line regimens. Methods: All evaluable patients treated with R-CHOP, R-CVP, or R-fludarabine (R-Flu)–containing regimens in the NLCS were included, except those with FL plus other lymphoma histology, non-FL histology, or those who progressed before first treatment or before being assigned to watchful waiting. Associations between baseline factors and choice of treatment (R-CHOP, R-CVP, or R- Flu–containing regimen), number of cycles received (≤4, 5–6, 7+), and completion of therapy were assessed using the Pearson chi-square test. Factors associated with risk of early discontinuation were assessed using logistic regression, and a generalized logits model was used to assess the relationship between baseline factors and number of cycles received. Kaplan-Meier methods and the log-rank test were used to estimate progression-free survival (PFS), overall survival (OS), and time to next treatment. Results: Among 1165 evaluable patients, a total of 648 received R-CHOP, 296 received R-CVP, and 221 received R-Flu combinations. Patient characteristics were similar between groups with the following exceptions: patients receiving R-CHOP were more likely to have grade 3 FL (38% vs 11% for R-CVP and 13% for R-Flu), and patients receiving R-CVP were older (25% ≥75 vs 8% for R-CHOP and 13% for R-Flu) and had higher Follicular Lymphoma International Prognostic Index (FLIPI) risk scores (50% poor FLIPI vs 41% for R-CHOP and 36% for R-Flu). The distribution of delivered cycles demonstrated a high degree of compliance with published regimens, with most patients receiving ≥5 cycles of treatment (R-CHOP 86%, R-CVP 81%, R- Flu 67%, P<.0001). The median cycle length was 21 days for both R-CHOP and R-CVP, and 29 days for the R-Flu regimens. Cycle intensity, defined as the expected cycle length (21 days for R-CHOP and R-CVP, and 28 days for R-Flu) divided by the actual cycle length, was between 0.9 and 1.1 for 68% of R-CHOP patients, 75% of R-CVP patients, and 45% of R-Flu patients. The percentage of patients with longer-than-expected time between cycles (cycle intensity <0.9) was similar for the 3 treatment groups; however, R-Flu patients were more likely to have shorter-than-expected time between cycles (24% vs 4% for R-CHOP and 3% for R-CVP). We sought to understand the reasons for patients receiving ≤4 cycles. Most patients who received ≤4 cycles were considered to have completed the intended duration of therapy (58% for R-CHOP, 62% R-CVP, and 75% R-Flu); rates of early discontinuation from the intended treatment were significantly less for patients receiving ≥5 cycles. Early discontinuation was associated with age ≥75 years and treatment with R-Flu (particularly in patients with grade 1–2 FL). Toxicity was the most commonly cited reason for early discontinuation (47% for R-CHOP, 46% for R-CVP, and 71% for R-Flu). The higher rate of R-Flu discontinuation due to toxicity is consistent with findings from other studies. Disease progression was rarely cited as the reason for early discontinuation. Time to retreatment was significantly shorter for patients receiving ≤4 cycles for patients receiving R-CHOP and R-CVP compared with patients receiving 5–6 cycles and 7+ cycles (P=.002 and P<.001 respectively; medians not yet reached). Delivery of ≤4 treatment cycles was associated with lower response rates (76% CR/PR vs 90% for 5–6 cycles and 92% for 7+ cycles) and worse PFS and OS, among patients who received R-CVP (all P<.01) but not among other regimens. Conclusions: Most patients with FL receiving chemoimmunotherapy in the NLCS completed ≥5 cycles of treatment. Most who received fewer cycles were considered to have completed therapy, and therapy commonly was given at or above the expected cycle intensity. Strategies to improve dose delivery appear unlikely to impact patient outcomes, except possibly in patients receiving R-CVP. Disclosures: Martin: Genentech: Speakers Bureau. Link:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrtek:Genentech: Employment. Dawson:Genentech, A Member of the Roche Group: Employment. Friedberg:Genentech: Membership on an entity's Board of Directors or advisory committees. Cerhan:Genentech: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech: Membership on an entity's Board of Directors or advisory committees.

AbstractThe impact of physical activity (PA) on lymphoma survival is not known. The association of PA and change in PA with overall (OS), lymphoma‐specific (LSS) and event‐free (EFS) survival was evaluated in a prospective cohort of newly diagnosed lymphoma patients (2002‐2012). We calculated Leisure Score Indexes (mLSI) from the self‐reported usual adult PA (baseline) and at 3‐years post‐diagnosis (FU3), grouping patients by active vs insufficiently active by the American Cancer Society PA guidelines. Associations of PA with survival were assessed using hazard ratios (HRs) and 95% confidence intervals (CI) from Cox models stratified by lymphoma subtype, adjusted for age, sex, baseline BMI, and comorbidity score with change scores further adjusted for baseline PA. Three thousand sixty participants were evaluable at baseline and 1371 at FU3. Active patients had superior survival from baseline [HR (CI): OS 0.82 (0.72‐0.94); LSS 0.74 (0.61‐0.90); EFS 0.92 (0.82‐1.02)] and FU3 [HR (CI): OS 0.64 (0.46‐0.88); LSS 0.32 (0.18‐0.59); EFS 0.82 (0.61‐1.10)] compared to insufficiently active. An increase in mLSI from baseline to FU3 (vs stable mLSI) was associated with superior OS (HR = 0.70, CI 0.49‐1.00) and LSS (HR = 0.49, CI 0.26‐0.94).The continuous change in mLSI at FU3 was significantly associated with OS, LSS and EFS; maintained across subgroups and appeared linear. Higher PA among lymphoma patients at diagnosis and 3 years is significantly associated with OS, LSS, and EFS. Increasing PA after diagnosis is significantly associated with improved OS and LSS supporting an important role for PA in lymphoma survivorship and the need for intervention trials.