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Abstract Abstract 3008 Poster Board II-984 Introduction: The erythropoiesis-stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) increase hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients (pts) with cancer chemotherapy-associated anemia (CAA). Extended-interval ESA dosing (i.e., administration less than once weekly) is a common practice with DA, which is FDA approved for dosing once every 3 weeks (q3wks); a previous study of the North Central Cancer Treatment Group suggested that EA can also be given less often than the FDA-approved once weekly schedule (Steensma DP et al, J Clin Onc 2006; 24:1079). The present study compared 2 different q3wks extended-interval EA regimens with weekly fixed-dose EA and with q3wks DA in pts with CAA. Patients and Methods: Eligible pts were receiving chemotherapy for a non-myeloid malignancy and had Hb <10.5 g/dL, ferritin >20 ng/mL, weight >40 kg and <150 kg, and ECOG performance score £2. Pts were randomized 1:1:1:1 to receive EA 40,000 Units subcutaneously (SC) once weekly (40K arm), EA 80,000 Units SC q3wks (80K arm), EA 120,000 Units SC q3wks (120K arm), or DA 500 mcg SC q3wks (DA arm), for 15 weeks. EA and DA were held for Hb >12 g/dL and restarted at a lower dose when Hb fell to '11.5 g/dL. All pts received ferrous sulfate 325 mg orally once daily, if tolerated. Quality of life (QOL) was measured using the Symptom Distress Scale (SDS), Brief Fatigue Inventory (BFI), FACT-An, and Linear Analogue Self Assessment (LASA) tools. The primary endpoint was the proportion of pts achieving Hb≥11.5 g/dL or increment of Hb>2.0 g/dL from baseline. Secondary endpoints included RBC transfusion requirements, adverse events (AEs), and QOL. Results: 239 pts (236 evaluable) enrolled at 10 MCCRC sites between Feb. 2007 and Dec. 2008; 62% of pts completed all study interventions. The median age of enrolled pts was 66 years; 42.4% were men, 91.5% had solid tumors, 26.7% had severe anemia (Hb <9.5 g/dL), and 44.9% were receiving platinum-containing regimens. Baseline characteristics were balanced between study arms, with the exception of gender (39% female for 40K, 60% for 80K, 43% for 120K, 26% for DA). There were no significant differences between treatment arms in the proportion of pts achieving a Hb response (68.9% for 40K, 61.7% for 80K, 65.5% for 120K, and 66.7% for DA; p>0.41 for all comparisons), but the median Hb increment from baseline was higher in the 40K and DA arms compared to the 2 extended dosing EA arms (40K-2.8 g/dL, 80K-2.0 g/dL, 120K-2.1 g/dL, DA-2.6 g/dL; p=0.005 for 40K vs 80K). Hb response was achieved more quickly in the weekly EA arm, but the difference was not significant (40K-32 days, 80K-50 days, 120K-49 days, DA-49 days; p>0.13). The proportion of patients transfused was similar between arms (40K-27.9%, 80K-33.3%, 120K-22.4%, DA-29.8%; p>0.49). There were no significant differences in QOL changes. Deaths were also similar between arms (40K-5 pts, 80K-7 pts, 120K-7 pts, DA-1 pt, p>0.10) and were primarily due to disease progression. AEs and serious AEs were comparable between study groups; grade 3/4 AEs were observed in 22% of pts in the 40K arm, 22% on 80K, 17% on 120K, and 13% on DA; p>0.56. The median total dose of EA used was highest in the 120K arm (40K-265,000 U; 80K-240,000 U; 120K-360,000 U; p=0.0009 for 40K vs 120K), while pts on the 40K arm were more likely to omit a dose due to a high Hb (40K-63.9% of pts omitted at least one dose; 80K-30.0%; 120K-34.5%; DA-43.6%, p<0.0001 for 40K vs 80K). Conclusion: Although there was no significant difference in the proportion of responding pts (the primary endpoint), Hb increments from baseline were moderately higher with the 2 FDA-approved regimens – weekly EA 40,000 Units, and q3wk DA 500 mcg – than with the extended dosing regimens. This study was supported by a grant from Centocor Ortho Biotech, Inc. to the MCCRC. Disclosures: No relevant conflicts of interest to declare.

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 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 We have taken a genetic strategy to define the mechanisms underlying the increased risk of VTE in myeloma patient treated with thalidomide using clinical trial data derived from the MRC, ECOG, Little Rock and HOVON trial groups. Baseline VTE rates in the MRC IX study, (CTD vs CVAD; n=748 no prophylactic anticoagulation), were 14%. Rates in both arms were equal but in the thalidomide arm, thrombotic events were all DVT’s or PE’s, whereas in the CVAD arm they split equally between line related and VTE’s. In the other comparison (CTD vs MP; n=542), the VTE rate was 17%, all in the thalidomide arm. Rates were similar or higher (30%) in the other trials depending on the intensity of treatment used. We carried out a nested case control on DNA from MRC IX on 90 VTE (45 thalidomide, 45 non-thalidomide related), matched to 180 controls. SNPlex analysis for 60 SNPs in the coagulation cascade, DNA repair, thalidomide, metabolism and myeloma specific pathways, identified 7 genes which affected risk (NBS1, MTHFR, Ku80, Cyp3A5, LGAL52 and IL12B). This suggests three major pathways contribute to the risk of thalidomide related VTE, metabolism of thalidomide, tumour responsiveness and some pro-thrombotic factors. These factors differ from non-thalidomide related risk where a strong pro-inflammatory response is most relevant. We tested this hypothesis further using an expanded panel of 3,404 SNPs (BOAC panel), using the Megalle system. Statistical analysis of this data defined the top 20 thalidomide and non-thalidomide associated SNPs, which were consistent with the initial hypothesis, the results of which exclude variation in the coagulation cascade as being a significant risk factor. We explored this hypothesis further using pathway-based analysis focussing on the MTHFR, DNA repair and WNT pathways on data from the ECOG, HOVON and Little Rock data sets. The biological relevance of the SNPs and genes identified was validated by correlating the level of expression using the Affymetrix U133 CHIP with genetic variation at the DNA level. To verify the relevance of DNA repair variability to tumour response further, we correlated gene expression profiling with response and again Ku80 was identified as one of a cluster of genes defining increased risk. The data suggests that the risk of thalidomide related VTE relates to rapid tumour lysis combined with a prothrombotic tendency, whereas in line related thrombosis, risk is dependent upon a strong proinflammatory response. We are building this genetic data into a clinical risk model in order to allow us to develop a rationale for intervention strategies.

Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 μg/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 μg/kg on days −3, −1, and 1, or 0.6 μg/kg on days −1 and 1. G-CSF, 5 μg/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34+ cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 × 106/kg (range, 1.3 to 17.6) versus 0.8 × 106/ kg (range, 0.3 to 4.2), P = .0003. The targeted minimum yield of 3 × 106CD34+ cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF–mobilized group versus 10% of G-CSF–mobilized patients (P = .001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P= .0001) and platelet recovery (day 9 v 10, P= .07) were accelerated, and fewer erythrocyte (3 v 4,P = .02) and platelet (4 v 5, P = .02) transfusions were needed compared with G-CSF–mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P < .0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 μg/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF–mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.

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 Background: Chronic GVHD contributes to morbidity and mortality after allogeneic transplantation. Several phase 2 and 3 open label studies suggested that ATLG (formerly referred to as ATG-F) reduces cGVHD without impacting relapse or survival. This report describes the first prospective randomized double blind phase 3 trial to assess the effect of ATLG (Neovii) when added to tacrolimus / methotrexate prophylaxis on cGVHD free survival. Patients and Methods: This study was conducted at 27 sites in the United States and Australia. 260 patients were randomized (132 placebo, 128 ATLG). 6 patients who were randomized never received ATLG/placebo (4 placebo and 2 ATLG). Data presented include the 128 placebo and 126 ATLG patients who underwent treatment and transplant. Patients were ages 18-65 years with a diagnosis of acute myeloid (AML, 64%) or lymphoblastic (ALL, 21%) leukemia in first or subsequent complete remission or myelodysplastic syndrome (MDS, 15%) with less than 10% marrow blasts. Median age was 48 years (18-65) with 55% males. All patients received 8/8 HLA (A, B, C, DR) allele matched unrelated products (80% mobilized peripheral blood, 20% bone marrow). Myeloablative conditioning was with cyclophosphamide and total body irradiation (Cy/TBI, 27%), busulfan and cyclophosphamide (Bu/Cy, 33%), or busulfan and fludarabine (Bu/Flu, 40%). All patients received tacrolimus starting on Day -1 and standard mtx on days 1, 3, 6, and 11 for GVHD prophylaxis. Patients received ATLG or placebo on Days -3, -2, -1 at an ATLG dose of 20 mg/kg per day (60 mg/kg total). The primary endpoint of the study was moderate/severe chronic GVHD free survival. cGVHD was scored by the investigator and then confirmed or overturned by an independent adjudication committee. Secondary endpoints included engraftment, acute GVHD , moderate/severe cGVHD, non-relapse mortality, GVHD and relapse free survival (GRFS), progression free (PFS) and overall survival (OS). The impact of ATLG on immune reconstitution was assessed in 91 patients. Results: Treatment arms were balanced with respect to age, diagnosis, remission status, cytogenetics, graft source (PB or BM), CMV serostatus and conditioning regimen. Median follow up of survivors was 745 days (61, 1425). Regarding the primary endpoint, there was no difference in 2 year moderate/severe cGVHD free survival between ATLG and placebo (48 vs 44%, p = 0.57), nor was there a difference in GRFS (Table 1). Neutrophil engraftment at Day 30 was less in the ATLG arm (85% vs 95%, p=0.00001). Grade 2 or higher infusion reactions were higher in the ATLG arm (16% vs 2.3%, p=0.0001). Reactivation of CMV was similar (27% vs 31%, p=0.58). The Day 180 cumulative incidence of grades 2-4 acute GVHD was lower in the ATLG arm (23 vs 40%, p = 0.003) as was the 2-year cumulative incidence of moderate/severe cGVHD (12 vs 33%, p = 0.000006). However, both 2-year OS and PFS were lower in ATLG treated patients (58 v 76% and 47 vs 67%, respectively) due in part to a higher incidence of relapse (32 vs 19%, p=0.068). Multivariable models confirmed that ATLG was associated with inferior OS, HR 1.85 (1.1-2.9, p=.0075) and PFS, HR 1.63 (1.1-2.41, p=0.015). We then conducted an unplanned post-hoc analysis and discovered a striking influence of conditioning regimen on outcomes. There were no differences in OS or PFS between ATLG and placebo arms in patients receiving Bu/Cy or Bu/Flu but a dramatic difference in patients receiving Cy/TBI conditioning (OS, 88% vs 48% p =0.006 and PFS, 75 vs 29%, p=0.007 in placebo and ATLG arms, respectively). 91 patients (44 ATLG, 47 placebo) participated in the immune reconstitution study. ATLG treatment was associated with lower CD3, CD4, and CD8 counts at Days 30, 100, and 360, respectively. In turn lower CD3, CD4, and CD8 counts assessed as time dependent variables were all associated with inferior OS and PFS as well as higher NRM (data not shown). Conclusion: In this first ever prospective, randomized, double blind trial of ATLG added to tacrolimus /methotrexate in recipients of matched unrelated donor grafts after myeloablative conditioning, there was no significant difference in 2 year moderate/severe cGVHD free survival or GRFS. ATLG did significantly reduce grades 2-4 acute and moderate/severe chronic GVHD. However, overall survival was higher in the placebo arm, driven mainly by patients who received Cy/TBI conditioning. Further analyses are needed to understand the proper role for ATLG in HCT. Disclosures Soiffer: Juno: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Porter:Genentech: Employment; Novartis: Patents & Royalties, Research Funding. Jagasia:Therakos: Consultancy. Szer:Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees. Glavin:Neovii Biotech: Employment. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

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: 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.

Abstract Background Inflammatory deregulation may be a major factor in cancer related symptoms (Dantzer Nature Rev Clin Oncol 2012). Improved symptoms in myelofibrosis (MF) patients treated with single arm ruxolitinib (JAK1/JAK2 inhibitor) studies has been correlated with normalization of selected cytokines increased pre-therapy (c-reactive protein, IL-1ra, MIP-1b, TNF-a, and IL-6; Verstovsek NEJM 2010). We sought to assess the impact of JAK1/JAK2 inhibitor therapy on cytokine levels and the relationship between cytokine levels and symptoms prior to and during JAK1/JAK2 inhibitor therapy in the phase III placebo controlled COMFORT-I trial (Verstovsek NEJM 2012). Methods Cytokine levels (89 cytokines measured at baseline and at weeks 4 and 24) and MF symptoms (assessed by MFSAF 2.0 – Mesa JCO 2013) were collected during the blinded phase of COMFORT-I. Patients were randomized to ruxolitinib vs. placebo. Plasma was used for the measurement of cytokines using Rules-Based Medicine, Inc. (Austin, TX) Human MAP panel. Associations between the MFSAF total symptom score (TSS) and log2-transformed cytokine data were investigated at baseline using Spearman correlations and linear regression. Mixed models were used to assess cytokine and TSS changes over time within each arm and overall. Logistic regression was used to assess the relationship between baseline cytokines and TSS response (>/=50% reduction from baseline) at week 24, and between week 4 cytokine changes and TSS response (>/=50% reduction from baseline) at week 24 within each arm and overall. Mixed and logistic regression models combining data across arms also included terms for visit, arm, and visit-by-arm interaction. All models also included age, gender, and body mass index (BMI). Given the large number of cytokines being investigated, p<0.001 was considered statistically significant. Cytokine values below the limit of detection were set at the lowest limit of detection and 25 cytokines were excluded from statistical analysis due to having more than 30% of data missing or below the limit of detection. Results Patients: 309 subjects were randomized in COMFORT-I with median age 68 (range 40-91), 46% female, 50% primary myelofibrosis, and 61% high risk. All 309 subjects had cytokines measured at one or more of the three visits included in this analysis, with 308 having cytokine values paired with a TSS score at the same visit. Cytokines at Baseline: At baseline, the highest Spearman correlations with symptomatic burden (as assessed by the TSS) were observed for APOA1 (rho=-.21) and FERRITIN (rho=-.20), followed by INTLK5, MIP1A, MMP3, INTLK2, MGB, INTLK1A, and INTLK7 with correlations between -.15 and -.17 (all p<0.01). After adjusting for age, sex, and BMI, VCAM1 and APOA1 were significantly associated with TSS at baseline. Cytokine and Symptom changes during trial: Changing levels of 5 cytokines were significantly associated with change of TSS over time beyond the change due to visit, arm, visit-by-arm interaction, age, sex and BMI including VCAM1, LEPTIN, TIMP1, B2MICG, and TNFRII. Within the placebo arm, only 5 cytokines significantly changed over time compared to 46 cytokines in the ruxolitinib arm (visit-by-arm interaction was significant for 43 in the overall models). VCAM1, B2MICG, and TNFRII were among the 5 cytokines which changed in the placebo arm, and VCAM1, LEPTIN, TIMP1, B2MICG, and TNFRII were among the 46 cytokines which changed in the ruxolitinib arm. No baseline cytokines and no changes in cytokines at week 4 univariately predicted week 24 TSS response within either arm at the p<0.001 level. Conclusions In the first serial assessment of MF symptoms and plasma cytokine levels in the conduct of a placebo controlled trial we found 5 cytokines in which improved levels correlated with decreased MF symptom burden in ruxolitinib treated patients. Development of a multivariate model for predicting symptom response, correlations with splenic response and impact on survival benefit of therapy is ongoing. Disclosures: No relevant conflicts of interest to declare.