Flinn, Ian W.

Abstract Abstract 127 Two- and three-drug regimens incorporating bortezomib (Velcade®, Vc), lenalidomide (Revlimid®, Rev), dexamethasone (Dex), and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC]), have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining Vc and Dex with Rev and Cy in a novel four-drug regimen (VDCR) may result in even greater activity with improved quality and duration of response. Results from the phase 1 dose-escalation portion of the multi-center EVOLUTION study showed that the VDCR regimen is a highly active and generally well-tolerated induction therapy in previously untreated MM patients (pts). Here we report the efficacy and safety of VDR, VDC, and VDCR from the non-comparative phase 2 portion of the study. Methods: Pts were randomized to receive up to eight 21-d cycles of VDR (Vc 1.3 mg/m2 d 1, 4, 8, 11; Dex 40 mg d 1, 8, 15; Rev 25 mg d 1–14) or VDC (VD as in VDR, plus Cy 500 mg/m2 d 1, 8) or VDCR (VDC plus Rev 15 mg d 1–14) as induction therapy, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles in all treatment arms. Pts received prophylactic antibiotics, acyclovir, transfusion support, and anticoagulants as required. Eligible pts wishing to undergo autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and undergo ASCT any time after cycle 4. Response categories were based on the IMWG Criteria with the addition of near complete response (nCR). Adverse events (AEs) were graded using the CTCAE v3.0. Results: In the VDR, VDC, and VDCR arms 42, 32, and 43 pts (including 6 pts treated at the maximum planned dose of Cy (500 mg/m2) from phase 1) have been treated, and 42, 31, and 33 are evaluable for response, respectively, as of data cut-off (31 July 2009). Median ages in the VDR, VDC, and VDCR arms were 60, 62, and 62 years, respectively; 62%, 63%, and 66% had International Staging System stage lI/III disease, and 38%, 25%, and 33% had Karnofsky Performance Status ≤80%, respectively. The median number of VDR, VDC, and VDCR cycles received is 4.5, 6, and 4, respectively (range 1–12). Best unconfirmed response rates are shown in the Table; patients categorized as very good partial response (VGPR) include those who have no measurable M-protein but have not yet had bone marrow assessments to confirm CR/nCR status. The overall rates of treatment-emergent AEs were 95%, 97%, and 88% for the VDR, VDC, and VDCR arms, respectively, with ≥grade 3 reported in 67%, 59%, and 65%. Peripheral neuropathy (PN) was reported as grade 2/3 in 12%/12% in the VDR, 31%/3% in the VDC, and 12%/9% in the VDCR arms; there was no grade 4 PN reported. Grade 3/4 neutropenia was reported in 5%/5%, 28%/13%, and 23%/9% of pts in the VDR, VDC, and VDCR arms, and grade 3/4 thrombocytopenia in 5%/2%, 9%/0%, and 5%/0% of pts, respectively. One case of grade 3 deep-vein thrombosis was reported in the VDCR arm. Overall rates of serious AEs were 24%, 13%, and 37% in the VDR, VDC, and VDCR arms, respectively. Two pts have died in the VDCR arm, both due to renal failure, considered possibly treatment-related. To date, 6 pts have undergone ASCT in the VDR arm, 5 in the VDC arm, and 3 in the VDCR arm. Median CD34+ yield was 4.7, 6.3, and 6.8 × 106/kg in the VDR, VDC, and VDCR arms, respectively. Conclusions: VDR, VDC, and VDCR are highly active and generally well-tolerated regimens in previously untreated MM. Response rates in the VDCR arm appeared somewhat higher than in the VDR and VDC arms at this early time point, although there also appeared to be higher rates of serious AEs, including possible treatment-related mortality in the VDCR arm. Following an interim analysis, dosing in the VDC arm was modified to include Cy on day 15 to examine if this will improve CR rates. Ten pts have been enrolled to date. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Milennium Pharmaceuticals Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Callander:Millenium: Research Funding. Noga:Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Raje:Celgene: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau. Shi:Millennium Pharmaceutical Inc.: Employment. Webb:Millennium: Employment, Equity Ownership. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Abstract 4591 Introduction: Clinicians and investigators appreciate the value of measuring HRQOL for monitoring CLL and the impact of treatments, and commonly use ECOG performance status (PS) and clinician-reported patient fatigue as surrogates for HRQOL in clinical practice. However, limited data exist on the relationships between PS, fatigue, and HRQOL in CLL patients (pts) undergoing treatment in clinical practices. We examined the associations between these measures and 3 psychometrically validated, patient-reported, HRQOL instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Methods: Data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving US practices. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by pts at enrollment using the BFI, EQ-5D, and FACT-Leu. Mean BFI, EQ-5D and FACT-Leu scores were analyzed by ECOG PS and clinician-reported fatigue. Differences in HRQOL scores between sub-cohorts were assessed by ANOVA. Results: HRQOL data were reported by 604 pts enrolled from 10 academic, 148 community, and 3 government centers. Pts were predominantly male (62%) and white (90%); mean age was 70 (standard deviation 11) years. BFI data (scale: 0 [no fatigue] - 10 [worst fatigue]) indicated that on average pts report that global fatigue, fatigue severity and fatigue-related interference worsen by ECOG severity (Table 1) and are statistically associated with clinician-reported fatigue (Table 2). Mean EQ-5D overall HRQOL as measured by a Visual Analogue Scale (VAS) from 0 (worst) to 100 (best) worsens by ECOG severity and is significantly worse in pts with fatigue. Mean EQ-5D domain scores (scale: 1 [no problem], 2 [some problems], 3 [incapacity]) indicated that pain/discomfort, mobility and usual activities increase in severity as ECOG worsens and in pts with fatigue. FACT-Leu domains except social/family were statistically worse with worse ECOG PS and in pts with fatigue. Conclusions: Initial results from Connect CLL® indicate that HRQOL worsens with worsening ECOG PS, especially in physical / functioning domains, pain/discomfort, and mobility, and worsens across multiple domains among pts whose physicians reported fatigue. Future analyses should be conducted on how HRQOL, PS and fatigue may change over time with changes in CLL, and how they are influenced by therapies. These results may serve as baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Patients (pts) with refractory aggressive non-Hodgkin lymphoma (NHL) have poor outcomes with currently available therapies, with a complete response (CR) rate of 8%, a partial response (PR) rate of 18%, and median overall survival (OS) of 6.6 months (mo) as demonstrated in the 635 pt SCHOLAR-1 meta-analysis (Crump, ASCO 2016; abstract 7516). ZUMA-1 is the first multicenter trial of anti-CD19 chimeric antigen receptor (CAR) T cells in refractory, aggressive NHL (NCT02348216). The phase 1 portion of ZUMA-1 showed ongoing CRs at 12+ mos in 43% of pts (Locke, ESMO 2016; abstract 1048O). The pivotal phase 2 portion of ZUMA-1 comprises 2 cohorts based on tumor type: DLBCL (cohort 1) and primary mediastinal B-cell lymphoma or transformed follicular lymphoma (cohort 2). Here, we present results of a prespecified interim analysis from cohort 1. Methods: Pts received a target dose of 2 × 106 anti-CD19 CAR T cells/kg after a low-dose conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) daily for 3 days. The primary endpoint is objective response rate (ORR) per 2007 IWG criteria. Key secondary endpoints include duration of response, frequency of adverse events (AEs), and levels of CAR T cells and serum cytokines. Key inclusion criteria include age ≥18 years, ECOG performance status (PS) 0-1, and refractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ≤12 mos after autologous stem cell transplant (ASCT). Pts must have received a prior anti-CD20 antibody and an anthracycline-containing regimen. A prespecified interim analysis was to be conducted to determine early efficacy with a nominal alpha level of 0.017 in 50 treated pts in cohort 1 with a minimum follow-up of 3 mos. Results: In total, 111 pts from 22 institutions were enrolled and leukapheresed, and 101 pts received KTE-C19. As of August 24, 2016, 51 pts in cohort 1 were eligible for analysis. Median age was 58 years (range, 25-76), 73% were male, 71% had ECOG PS 1, 78% were refractory to ≥2 lines of therapy, 20% relapsed ≤12 mos of ASCT, and 61% were treated with ≥3 lines of prior therapy. KTE-C19 was successfully manufactured in 99% of pts enrolled. Average turnaround time from apheresis to receipt of KTE-C19 at the clinical site was 17.4 days. With an ORR of 76%, the study met the primary endpoint (P<0.0001; exact binomial test comparing observed ORR to a historical control assumption of 20%), with 47% CRs and 29% PRs. 92% of responses occurred within the 1st mo, and 39% of pts had ongoing responses (CR in 33%) at 3 mos. Responses were seen across key covariates, including refractory subgroup (refractory to chemotherapy=76%, relapse post ASCT=80%). Kaplan-Meier estimates of progression-free survival at 1 and 3 mos were 92% and 56%, respectively. The most common grade ≥3 treatment-emergent AEs were neutropenia (67%), anemia (39%), thrombocytopenia (29%), febrile neutropenia (27%), and encephalopathy (24%). Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 20% and 29% of pts, respectively. There was 1 grade 5 KTE-C19-related event of hemophagocytic lymphohistiocytosis. CAR T cells expanded within 14 days of KTE-C19 infusion, and peak expansion was associated with ongoing response at mo 3 (P=0.008). Pts who developed grade ≥3 neurological events had increased serum levels of IL-15 (P=0.0002), IL-6 (P=0.003); IL-10 (P=0.009) and IP-10 (P=0.0003). Cytokines/chemokines returned to baseline levels in most pts by day 28. Data from 93 pts with at least 1 mo of follow-up at the data cutoff will be presented. Conclusions: ZUMA-1 is the first reported multicenter trial of CAR T cell therapy in pts with refractory aggressive NHL. KTE-C19 induced a nearly 6-fold higher CR rate compared to historical outcomes in SCHOLAR-1. Efficacy strongly associated with peak CAR T levels. Central manufacturing, logistics, and AE management were successfully implemented across 22 sites, most with no prior CAR T therapy experience. Results from cohort 2 of ZUMA-1 are also presented (Abstract #998). KTE-C19 demonstrated significant clinical benefit in pts with no curative treatment options. Supported in part by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program®. Drs Neelapu and Locke contributed equally to this study. Disclosures Neelapu: Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Locke:Kite: Membership on an entity's Board of Directors or advisory committees. Miklos:pharmacyclics: Research Funding; Kite Pharma: Research Funding; Roche: Research Funding; Novartis: Research Funding. Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Siddiqi:Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau. Lin:Mayo Clinic: Employment; Janssen: Research Funding. Timmerman:Bristol-Myers Squibb, Kite Pharma, Valor Biopharmaceuticals, Janssen: Research Funding; Seattle Genetics, Genmab, Celgene: Consultancy, Honoraria. Goy:COTA: Membership on an entity's Board of Directors or advisory committees; Janssen/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research funding for clinical trials through institution, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research funding for clinical trials through institution; Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Other: Research funding for clinical trials through institution. Smith:Abbvie: Research Funding; Celgene: Honoraria; Spectrum: Honoraria; Genentech: Honoraria. Deol:Jazz Pharmaceuticals: Consultancy. Avivi:Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche. Westin:Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Chavez:Janssen: Speakers Bureau. Levy:Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding. Reagan:Seattle Genetics: Research Funding. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Elias:Kite: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership.

Abstract INTRODUCTION Recurrent somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) confer gain-of-function activity in cancer cells, resulting in accumulation of the oncometabolite, D-2-hydroxyglutarate (2-HG). High levels of 2-HG result in epigenetic changes and impaired cellular differentiation. IDH mutations have been identified in multiple solid tumors and hematologic malignancies. Approximately 6-10% and 9-13% of adults with acute myeloid leukemia (AML) carry mutations in IDH1 (mIDH1) or IDH2 (mIDH2), respectively. AG-120 is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH1 mutant enzyme under evaluation in multiple ongoing single agent and combination clinical trials [NCT02074839, NCT02073994, NCT02632708, NCT02677922]. This is the first report of IDH1 mutation clearance assessed by variant allele frequency (VAF) analysis using next-generation sequencing (NGS) in patients treated on the dose escalation portion of the first-in-human phase 1 study [NCT02074839]. METHODS Patients with advanced mIDH1-positive hematologic malignancies received AG-120 as a single agent orally once daily (QD) or twice daily (BID) continuously in 28-day cycles. Primary objectives were determination of safety, maximum tolerated dose (MTD), and selection of a dose schedule for expansion cohorts and future studies. Secondary objectives included clinical activity assessed by investigators using modified 2003 International Working Group Criteria in AML. Determination of mIDH1 VAF was performed using the FoundationOne® Heme test on mononuclear cells from the bone marrow or peripheral blood at screening and subsequent time points on study. This NGS assay reports IDH1 mutations for samples with VAF ≥1%, with median coverage 500X. Patients with IDH1 mutational clearance (IDH1-MC) were defined as having mIDH1 at baseline and at least one on-study sample with no reported mIDH1. RESULTS Seventy-eight patients were treated in the dose escalation portion, which is now closed to enrollment. As of the data cut-off of May 12, 2016, the median duration on treatment was 3.2 months and 9 (11.5%) patients remain on treatment, with an additional 8 (10.3%) patients transitioned to stem cell transplant. Doses ranged from 300-1200 mg QD with 1 cohort at 100 mg BID. Though the MTD was not reached, the recommended phase 2 dose was determined to be 500 mg QD. The majority of adverse events (AEs) were grade 1 and 2, the most common (≥30%) being diarrhea, fatigue, and nausea; the most common grade ≥3 AEs (≥15%) were febrile neutropenia, anemia, leukocytosis and pneumonia. The most common serious AEs were febrile neutropenia (16.7%) and pneumonia (12.8%). The overall response rate (ORR) was 38.5% (n=30), with 17.9% (n=14) achieving a complete remission (CR). Longitudinal mIDH1 VAF data were available for 51 patients; of these, 22% (n=11) achieved a CR. IDH1-MC was observed in 27.3% (3/11) patients who achieved CR (Figure 1). In contrast, only 1/40 patients who did not achieve CR experienced IDH1-MC. This occurred in a patient with an initially low mIDH1 VAF who had clinical progression despite IDH1-MC (Figure 1, bottom right). In all 3 patients with CR who achieved IDH1-MC, an initial increase in mIDH1 VAF, or early peak, was observed prior to IDH1-MC, suggesting that early clonal expansion might have occurred as part of the mechanism of action of AG-120. CONCLUSION This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance as determined by NGS. Further analysis of the mutational profiles is planned. AG-120, a potent, selective, oral inhibitor of mIDH1 continues to demonstrate a well-tolerated safety profile in patients with advanced hematologic malignancies, and induced objective single-agent durable responses. The data continue to support the efficacy and safety of single agent AG-120 and provide evidence that the underlying biology of the disease is altered by treatment. Figure 1. VAF analysis using FoundationOne® Heme NGS assay in 4 AML patients with IDH1-MC treated with AG-120 Figure subscript: Y-axis is mIDH1 VAF, x-axis is days on treatment. Text indicates investigator-assessed clinical response. CR, complete remission; CRi, CR with incomplete neutrophil recovery; CRp, CR with incomplete platelet recovery; R/R, relapsed/refractory; SD, stable disease; PD, progressive disease; *post-transplant sample Figure 1. VAF analysis using FoundationOne® Heme NGS assay in 4 AML patients with IDH1-MC treated with AG-120. / Figure subscript: Y-axis is mIDH1 VAF, x-axis is days on treatment. Text indicates investigator-assessed clinical response. CR, complete remission; CRi, CR with incomplete neutrophil recovery; CRp, CR with incomplete platelet recovery; R/R, relapsed/refractory; SD, stable disease; PD, progressive disease; *post-transplant sample Disclosures DiNardo: Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. de Botton:Novartis: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Servier: Consultancy; Pierre Fabre: Consultancy. Stein:Agios: Other: advisory board; Celgene: Other: advisory board; Novartis: Other: advisory board. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Pollyea:Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding; Ariad: Other: advisory board; Glycomimetics: Other: DSMB member; Celgene: Other: advisory board, Research Funding. Fathi:Bexalata: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding. Altman:Syros: Honoraria; BMS: Honoraria; Janssen Pharmaceuticals: Honoraria; Novartis: Honoraria. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Foran:novartis: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; karyopharm: Honoraria; medscape: Honoraria; pfizer: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Pigneux:Sunesis: Consultancy, Honoraria; Agios: Consultancy, Honoraria. Kantarjian:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Liu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Sacolick:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yen:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hurov:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Choe:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Wu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Stone:Amgen: Consultancy; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy.

Abstract Introduction: The median age at diagnosis for CLL pts in the US is 72 years. As clinical trials in CLL have largely enrolled younger pt populations, data on disease and pts' characteristics, patterns of care, prognosis, and molecular features in aged CLL pts are limited. With this in mind, we conducted a prospective study to update critical demographic data and patterns of care for aged CLL pt. Patients and Methods: Connect®-CLL is a US-based prospective, longitudinal, multi-center, observational registry that is aimed at understanding patterns of CLL management without a study-specific intervention. We enrolled pts treated at an academic (n=155) or community (n=1340) setting between 2010 and 2014. Eligible pts were adults with a clinical diagnosis of CLL who required therapy 2 or less months after enrollment. Data on demographics, baseline characteristics, and treatment selection are presented here using descriptive statistics. Continuous variables are reported using appropriate measures of dispersion and central tendency (means, medians, ranges and standard deviations) while categorical variables are summarized as number and percentage of the analysis population. Results: Of 1495 enrolled pts, 457 (30.5%) were ≥75 years (57.3% males, 94.2% white). Rai stage III/IV was noted in 33% and B symptoms (predominantly fatigue (58.4%)) were observed in 68.1%. These and other clinical baseline characteristics appeared similar to pts younger than 75 years except that older pts had more prior malignancies (33.5% vs. 19.8%) and co-morbidities (69.3% vs. 53.6%). Cardiac, neurologic, and renal disorders were the most common morbidities in pts ≥75 years (11.5%, 8.8%, and 4.6% respectively). Imaging studies were performed in 157 (60.2%) older pts and in 416 (65.7%) pts less than 75 years prior to initial therapy. Percentage of pts with bulky nodes (> 5 cm) by imaging was similar in the two groups, 19.3% overall. Prognostic biomarker data were available on 247 pts (178 (72%) <75 years; 69 (28%) ≥75 years). While a higher proportion of older pts had CD38+ CLL (55.1% vs. 40.5%, P=0.038), the proportions of patients with ZAP-70+ CLL were similar between the two groups. In total, 137 (9%) older and 378 (25%) younger pts had 17p and 11q analysis by FISH at enrollment prior to first-line therapy. Of these, 27.0% of pts ≥75 years and 20.6% of pts <75 years had a deletion of either 17p or 11q (P=0.125). Out of all pts enrolled in the registry, 894 (60%) received first-line treatment (261 (29%) pts ≥75 years and 633 (71%) <75 years) as their indication for study entry. Amongst these treated pts, interim analysis shows (data cutoff date: 25 June 2014) progressive marrow failure was more commonly used as the indication for therapy in older pts compared to younger pts (52.1% vs. 38.5%; P<0.001), while splenomegaly was a more common cause for therapy in younger pts (16% vs. 9%; P<0.01). Rai stage III/IV at time of first therapy was 46% and 49% for younger and older pts, respectively. Progressive lymphocytosis was used as the indication for therapy in one third of pts regardless of age. Seventy-four percent of older CLL pts received first-line therapies containing rituximab (R) vs. 85% in pts <75 years (P<0.0001). R-bendamustine was the most common first-line regimen for CLL pts ≥75 (23.4%) while FCR was more commonly given to pts <75 years (32.5%). R-monotherapy was used in 18.8% of older pts versus 9.5% in pts <75 years (P<0.0001). Of note, approximately 25% of CLL pts ≥75 years did not receive R-based regimens for initial therapy. Conclusions: Connect®-CLL is the largest prospective, multicenter CLL registry in the United States. CLL Pts ≥75 years more frequently overexpress CD38 and may more commonly demonstrate high risk cytogenetics by FISH, although the difference did not reach statistical significance. Pts ≥75 years also more commonly had co-morbid diseases, and surprisingly 25% did not receive first-line R-based therapy. CLL pts are rarely included in front-line clinical trials (<3%). Given that novel therapies are increasingly available for CLL patients a continued analysis is warranted to determine their use in elderly vs younger patients as well. A longer follow up is needed to evaluate the impact of these findings on outcomes. Disclosures Nabhan: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide in CLL. Kay:Celgene: Research Funding. Mato:Genentech, Celgene, Millenium: Speakers Bureau. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kipps:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weiss:Celgene: Consultancy. Flinn:Celgene: Research Funding. Swern:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Kristen:Celgene: Employment, Equity Ownership. Flowers:Celgene, Prescription Solutions, Seattle Genetics, Millennium (unpaid), Genentech (unpaid) : Consultancy; Gilead, Spectrum, Millennium, Janssen: Research Funding.

Abstract Abstract 873 Introduction: Clonal chromosomal anomalies have been well-characterized in the blood cells of patients with Chronic Lymphocytic Leukemia (CLL) and other hematological malignancies. However, the frequencies and types of chromosomal anomalies found in “normal” people (i.e. no history of hematological cancer) are much less well known. Here we compare chromosomal anomalies in untreated CLL patients with those found in a large sample of people (n>50,000) recruited for genome-wide association studies in the Gene Environment Association Studies (GENEVA) consortium. This comparison provides information about the extent to which people without a prior history of hematological cancer have chromosomal anomalies that are characteristic of CLL. Methods and Results: The anomaly detection method focused on acquired, rather than inherited, chromosomal anomalies identified in whole blood samples. The method and results for the GENEVA subjects were published recently (Laurie et al. 2012, Nat. Gen. 44:642–650). The same method was applied to pre-treatment samples from 220 CLL patients from US Intergroup Trial E2997 of the Eastern Cooperative Oncology Group (ECOG). Acquired anomalies were detected as mosaic mixtures of normal disomic cells along with cells containing autosomal anomalies consisting of large (generally > 1 Mb) deletions, duplications and/or acquired uniparental disomy (UPD). Detection requires a large fraction of cells with the same abnormal karyotype (>5–10%), which is presumably of clonal origin. The subjects (of all ages) came from 12 different GENEVA studies, which addressed a variety of health conditions not directly related to hematological cancer (e.g. addiction and glaucoma). DNA was extracted mainly from blood samples (or, in 8% of subjects, from buccal/saliva samples) and genotyped on Illumina SNP mircroarrays. Clonal mosaic anomalies were detected from change points in intensity and genotype data (B Allele Frequency and Log R Ratio). We found 514 anomalies in 404 GENEVA subjects out of 50,222 examined (0.8% of subjects), although the prevalence increased with age. Clinical data from about 75% of subjects with a clonal chromosomal abnormality revealed that only a small fraction (2.8%, 95% CI=1.0 – 4.7%) had a record of prior hematological cancer. In the ECOG study, blood samples from 220 CLL patients enrolled in protocol E2997 were genotyped on the Illumina HumanOmni1-Quad_v1 array and clonal mosaic chromosome anomalies were detected using the GENEVA method. Chromosomal anomalies typical of CLL also were identified using interphase FISH (i.e. 6q23.3-, 11q22-, 12q15+, 13q14-, 17p13-) as previously reported (Grever, JCO 25:799-804). We found 489 anomalies in 148 patients of the 220 examined (67% of patients). The anomalies detected by FISH and SNP microarray were highly concordant (>98%). Although, the most common recurrent anomalies occurred on chromosomes 6, 11, 12, 13 and 17 in regions that span the FISH probes (except for chromosome 6), a majority of the anomalies detected by SNP data (74% of 489) were not detected by the CLL FISH panel. The frequency of large chromosomal anomalies was much higher in CLL patients than in GENEVA (67% versus 0.8% of subjects) and the overall composition of anomaly types found was also different. The fraction of anomalies consisting of acquired UPD was substantially higher in GENEVA subjects than in ECOG (34.0% versus 10.6%), while deletions were less common in GENEVA (50.1% versus 72.4%) and duplications were similar (15.6% versus 17.0%) (Chi-squared test p-value=3 × 10−18). We compared the most commonly deleted regions (CDR) on each chromosome across studies. In the ECOG CLL patients, four chromosomes each had 10 or more overlapping deletions in their top CDR (6, 11, 13 and 17), which span the FISH probes (except for chromosome 6). The GENEVA subjects also had CDR on chromosomes 11, 13 and 17, which overlap those in ECOG. In addition, GENEVA had CDR spanning genes or regions implicated in myeloid malignancies, including DNMT3a on 2p, TET2 on 4q, PRAME on 22q, and a region on 20q13. Conclusions: These genotyping results of >50,000 subjects suggest clonal chromosomal anomalies may represent precursor states, or perhaps undiagnosed or unrecorded cases, of a variety of hematological malignancies. Further studies to validate these findings and explore the natural history of these genetic defects in individuals without hematologic malignancy are warranted. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.

Abstract 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.

Background:Lenalidomide plus rituximab (R2) has established efficacy and a tolerable safety profile in patients with previously untreated and relapsed/refractory (R/R) indolent NHL. This includes patients with marginal zone lymphoma (MZL) who are generally treated in a similar manner to follicular lymphoma (FL).Aims:Primary results for the AUGMENT study in R/R FL grade 1–3a and MZL showed significantly improved progression‐free survival (PFS) for R2 over R/placebo in the overall population and in the subgroup analyses, with the exception of the MZL subgroup. Given the small sample size for MZL patients, post hoc analyses of baseline characteristics and univariate/multivariate analyses of PFS were conducted to examine possible explanations for these results.Methods:The phase III AUGMENT study randomized patients 1:1 to R2 (lenalidomide PO 20 mg/day (d), d1–21/28 X12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2–5) or rituximab‐placebo (R/placebo; same dosing schedule). PFS by 2007 IWG (without PET) was the primary endpoint. Post hoc Cox regression models were used for univariate analysis of one risk factor and multivariate analyses including treatment arm and significant risk factors (P < 0.05) from the univariate analyses.Results:A total of 63/358 (18%) MZL patients were part of the overall study population, including n = 14/16 MALT, n = 9/6 splenic, and n = 8/10 nodal MZL subtypes for respective R2 and R/placebo arms. Numerical differences between treatment arms for baseline demographics and disease characteristics for MZL patients favoring the R/placebo arm were: fewer R2 patients had an ECOG score of 0 (55% R2 vs 72% R/placebo), and more R2 (vs R/placebo) patients were older (≥65 y: 68% vs 59%; ≥70 y: 42% vs 38%), were refractory to the last prior regimen (13% vs 3%), had Ann Arbor stage IV disease at enrollment (65% vs 41%), high‐risk MALT‐IPI score (50% vs 19%), elevated LDH (29% vs 19%), B symptoms (13% vs 3%), and high tumor burden per GELF criteria (65% vs 56%). The most common grade 3/4 AEs for MZL patients receiving R2 vs R/placebo, respectively, were neutropenia (47% vs 16%), pneumonia (3% vs 13%), and leukopenia (10% vs 0). A total of 5 deaths occurred in the R2 arm (most associated with progression of disease; 2 deaths occurred early at 3 and 13 days after randomization [one prior to receiving R2 and one 2 days after treatment initiation]) and 2 in the R/placebo arm. Despite worse prognostic features, best response was improved with R2 (vs R/placebo) with ORR = 65% vs 44% (P = 0.13) and CR = 29% vs 13% (P = 0.13), although neither were statistically significant. Improved response rates did not translate into a survival advantage for R2. Median PFS for MZL patients was 20.2 mo R2 vs 25.2 mo R/placebo (HR = 1.00; 95% CI, 0.47–2.13; P = 1.0). Univariate analyses showed that several baseline factors were prognostic for MZL patients (P < 0.05): Ann Arbor stage IV, elevated LDH, and unfit for chemotherapy (Table). Multivariate analyses adjusting for the imbalance in these 3 significant prognostic factors showed an adjusted PFS HR of 0.51 (95% CI, 0.20–1.28) favoring the R2 arm, similar to the PFS HR in the overall population (HR = 0.46; 95% CI, 0.34–0.63). The univariate and multivariate analyses suggested that the imbalance in baseline prognostic factors impacted PFS results for MZL patients.Summary/Conclusion:Overall, these findings suggest that the PFS results in MZL patients were negatively impacted by the imbalance in baseline prognostic factors and more aggressive disease in the R2 over the R/placebo arm.image