Citations

Introduction: The phase 3 international, randomized, double-blind ROBUST clinical trial (NCT02285062) compared progression-free survival between patients with previously untreated ABC-type DLBCL treated with placebo plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (placebo-R-CHOP) versus lenalidomide + R-CHOP (R2-CHOP) for 6 21-day cycles. HRQoL, as measured by the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EuroQoL 5-dimension 3-level (EQ-5D-3L) patient-reported questionnaires, was evaluated as a secondary endpoint for the 2 treatment arms. Methods: For each treatment group, FACT-Lym and EQ-5D-3L scores were measured at baseline (BL), mid-, end-of-treatment (EOT), and post-treatment, in 12-week intervals from Week 34 onward. Patients were evaluated if they had completed BL and ≥ 1 post-BL calculable FACT-Lym subscale measurements. Non-inferiority (NI) of R2-CHOP versus placebo-R-CHOP was measured for 4 key FACT-Lym subscales: Physical Well-Being (PWB), Additional Concerns (AC), Functional Well-Being (FWB), and Trial Outcome Index (TOI). NI was assessed at EOT (typically 3-4 weeks after completing Cycle 6) and at post-treatment follow-up at Week 34 by analysis of covariance (ANCOVA). The NI margins were prespecified as 1 less than the higher published minimal important difference (MID) for each subscale. Since a range of MIDs have been published, a more conservative value was also used as a sensitivity analysis. Time to improvement (TTI), using published responder definitions, was also assessed for the FACT-Lym subscales. EQ-5D-3L scores were summarized descriptively. Results: Demographic and baseline disease characteristics were balanced across the 2 treatment arms (N = 285 per arm). The percentage of patients who completed the FACT-Lym out of the expected population remained > 85% at all time points with > 50 patients still on the study in each treatment arm up to Week 142. Completion rates and reasons for missing assessments were balanced across the 2 treatment arms. FACT-Lym subscale scores were generally higher after EOT, similar for both treatment groups, and mean changes from BL were close to or above MID (where defined), except for the Social/Family Well-Being subscale. Mean differences in FACT-Lym TOI between treatment arms are shown in Table 1. As positive treatment differences favor R2-CHOP and -10 was the predefined NI margin, NI was demonstrated for the FACT-Lym TOI subscale at both EOT and Week 34 assessments. Superiority of R2-CHOP was demonstrated at EOT as the confidence interval (CI) lies completely above 0 (P < 0.04); however, this difference was not clinically meaningful. Furthermore, NI was also demonstrated when using the sensitivity analysis margin of -4.5. ANCOVA models were also fitted for the other key subscales of PWB, AC and FWB (Table 2). NI was demonstrated for all NI margins at both time points for the PWB and AC subscales. The FACT-Lym FWB subscale demonstrated NI for both margins at EOT and Week 34 for the primary NI margin of -2 based on the MID minus 1, but did not demonstrate NI when an NI margin of -1, based on an alternative published MID, was used. The TTI curves and associated summary statistics were similar for the 2 treatment arms, with a median TTI for the FACT-Lym TOI of 21 weeks (95% CI 15-22) for patients treated with R2-CHOP and 18 weeks (95% CI 15-22) for patients treated with placebo-R-CHOP. Mean EQ-5D-3L visual analogue scale (VAS) and Utility Index (UK weights) change from baseline scores were higher in both treatment arms and the mean changes were above, or close to, the published MID (7 for VAS, 0.1 for Utility Index) at EOT assessments. Prespecified sensitivity and subgroup analyses supported the conclusions from the primary HRQoL analyses. Conclusions: The predefined NI levels were met for the 4 key FACT-Lym subscales. Similar results were observed across the other HRQoL assessments, sensitivity, and subgroup analyses. Adding lenalidomide to the R-CHOP regimen did not adversely affect the HRQoL of patients with DLBCL as measured by FACT-Lym and EQ-5D-3L. These data serve as a benchmark for future clinical trials combining next-generation immunomodulatory drugs with standard R-CHOP to improve clinical efficacy while maintaining HRQoL in patients with DLBCL. HRQoL analyses should become an integral part of future clinical trials of novel combination regimens in DLBCL. Disclosures Chiappella: Roche: Speakers Bureau; Teva: Speakers Bureau; Servier: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau. Cocks:Adelphi Values: Employment; Amgen: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy; Endomag Ltd.: Consultancy. Greenwood:Adelphi Values: Employment. Williams:Adelphi Values: Employment. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Janssen: Consultancy, Research Funding. Yamamoto:SymBio: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria; Sanofi: Honoraria; Astra-Zeneca: Consultancy, Research Funding; Sumitomo Dainippon: Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Gilead Sciences: Research Funding; Solasia Pharma: Research Funding; Bayer: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; ARIAD: Research Funding; Pfizer: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Kyowa Kirin: Honoraria; MSD: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; Incyte: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Jurczak:Bayer: Research Funding; Takeda: Research Funding; Gilead: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Incyte: Research Funding; Celgene Corporation: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding. Özcan:Sanofi: Other: Travel support; Abdi Ibrahim: Other: Travel support; BMS: Other: Travel support; Takeda: Honoraria, Other: Travel support, Research Funding; Archigen: Research Funding; Roche: Other: Travel support, Research Funding; Bayer: Research Funding; Janssen: Other: Travel support, Research Funding; Celgene Corporation: Research Funding, Travel support; AbbVie: Other: Travel support, Research Funding; MSD: Research Funding; Novartis: Research Funding; Jazz: Other: Travel support; Amgen: Honoraria, Other: Travel support. Belada:Roche: Consultancy; Gilead Sciences: Consultancy; Takeda: Consultancy. Margunato-Debay:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Zhai:Celgene Corporation: Employment, Equity Ownership. Braverman:Celgene Corporation: Employment. Vitolo:Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

Abstract Implanted neural stimulation and recording devices hold vast potential to treat a variety of neurological conditions, but the invasiveness, complexity, and cost of the implantation procedure greatly reduce access to an otherwise promising therapeutic approach. To address this need, a novel electrode that begins as an uncured, flowable prepolymer that can be injected around a neuroanatomical target to minimize surgical manipulation is developed. Referred to as the Injectrode, the electrode conforms to target structures forming an electrically conductive interface which is orders of magnitude less stiff than conventional neuromodulation electrodes. To validate the Injectrode, detailed electrochemical and microscopy characterization of its material properties is performed and the feasibility of using it to stimulate the nervous system electrically in rats and swine is validated. The silicone‐metal‐particle composite performs very similarly to pure wire of the same metal (silver) in all measures, including exhibiting a favorable cathodic charge storage capacity (CSC C ) and charge injection limits compared to the clinical LivaNova stimulation electrode and silver wire electrodes. By virtue of its simplicity, the Injectrode has the potential to be less invasive, more robust, and more cost‐effective than traditional electrode designs, which could increase the adoption of neuromodulation therapies for existing and new indications.

Despite its rank as the fourth healthiest state in the United States, Minnesota has clear cardiovascular disease disparities between African-Americans and whites. Culturally-tailored interventions implemented using community-based participatory research (CBPR) principles have been vital to improving health and wellness among African-Americans. This paper delineates the establishment, impact, and lessons learned from the formation of a community steering committee (CSC) to guide the Fostering African-American Improvement in Total Health (FAITH!) Program, a CBPR cardiovascular health promotion initiative among African-Americans in Minnesota. The theory-informed CSC implementation process included three phases: (1) Membership Formation and Recruitment, (2) Engagement, and (3) Covenant Development and Empowerment. The CSC is comprised of ten diverse community members guided by mutually agreed upon bylaws in their commitment to FAITH!. Overall, members considered the CSC implementation process effective and productive. A CBPR conceptual model provided an outline of proximal and distal goals for the CSC and FAITH!. The CSC implementation process yielded four lessons learned: (1) Have clarity of purpose and vision, (2) cultivate group cohesion, (3) employ consistent review of CBPR tenets, and (4) expect the unexpected. A robust CSC was established and was instrumental to the success and impact of FAITH! within African-American communities in Minnesota.

Abstract Abstract 4608 Background: FCR has been a preferred 1st line therapy approach in CLL for the past decade. However it is associated with substantial toxicity and not recommended in NCCN guidelines for patients over age 70. We studied the impact of age, co-morbidities, and tempo of disease on 1st line therapy prescribing preferences of American hematology-oncology physicians (AHOP) for patients with CLL. Methods: During Feb-March 2012, prescribing preferences of 325 individual AHOP were assessed using a proprietary, live, case-based market research tool (Challenging Cases™). A core case scenario was constructed with variations based on altered age, co-morbidities, and tempo of disease progression prior to initial therapy. Preference data were acquired using blinded audience response technology. Responses for each scenario were obtained prior to any display of participant selections. All sources of research support were blinded. Core scenario: 67y male; CD 38+, ZAP 70+, del 13q and del 11q CLL, adenopathy, lymphocytosis, splenomegaly, anemia (Hgb 9.5 gm) but no thrombocytopenia. Co-morbidities: medication-controlled hypertension, moderate restrictive airways disease, and type 2 diabetes managed with metformin. Modified scenario: same clinical presentation except the patient is 72 years of age. Slower tempo of disease scenario: age 68y, time frame of observation without treatment 3 years from diagnosis, now with disease progression, anemia 10.9 gms, FISH only del 13q. Results: A progressive decrease in preference for FCR and commensurate rise in preference for BR as first line therapy occurs as age increases and co-morbidities are present (p<0.001). See table 1 Conclusion: As age crosses the 70 year threshold and as co-morbidities complicate therapy, there is a statistically significant increase in preference among AHOPs for prescribing bendamustine-rituximab as initial management for patients with RAI stage III CLL. Disclosures: Green: Xcenda: Employment; Teva: Consultancy, ownes publically traded shares in Teva Pharmaceuticals through 3rd party investment advisors, ownes publically traded shares in Teva Pharmaceuticals through 3rd party investment advisors Other. Williams:Xcenda: Honoraria. Willey:Xcenda: Employment. Scharf:Xcenda: Employment. Neely:xcenda: Employment. Foran:Xcenda: Honoraria.

Abstract Introduction Patients with mantle cell lymphoma (MCL) typically respond to initial therapy and almost inevitably relapse with frequent chemoresistance over time and poor outcome. Multiple phase II studies have established the efficacy and safety of lenalidomide, an immunomodulatory agent with tumoricidal and antiproliferative properties, in relapsed/refractory MCL. The prospective phase II multicenter MCL-001 “EMERGE” study led to FDA approval of lenalidomide for patients with relapsed/refractory MCL after 2 prior treatments, that included bortezomib. The activity of lenalidomide was seen regardless of MIPI, number of prior therapies, prior high dose therapy, bulky disease or high tumor burden. One of the most established prognostic factors in MCL is the proliferation index Ki67 (MIB1), now confirmed both in standard and dose-intensive high-dose therapy strategies. We present here longer follow-up of efficacy and safety from the MCL-001 study in patients relapsed/refractory to bortezomib and the potential relationship between Ki-67 and efficacy outcomes. Methods Patients with heavily pretreated MCL, that included prior bortezomib, received lenalidomide 25 mg/day PO, days 1-21 in 28-day cycles until disease progression or intolerability. Primary study endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety. Response rates and time-to-event data were analyzed by independent central reviewers per modified IWG criteria and Kaplan-Meier estimates respectively (data cut-off March 20, 2013). Ki-67 was examined as an exploratory endpoint by immunohistochemistry for 81/134 patients (60%) either performed on biopsy samples for 24 patients, or based on the Ki-67 scores reported in local pathology reports for 57 patients. Results Median age for the enrolled intent-to-treat patient population (N=134) was 67 years (range, 43-83; 63% ≥65 years). The median number of previous therapies was 4 (range, 2-10; 78% received ≥3), 93% stage III/IV, and 72% were <6 months from last prior treatment. At a median follow-up of 13.2 months, the ORR was 28% (CR/CRu 8%), with a median DOR of 16.6 months (95% CI, 9.2-26.7; median not reached in patients with CR/CRu) by central review. Median TTR was 2.3 months (95% CI, 1.7-13.1), with a median time to CR/CRu of 4.1 months (95% CI, 1.9-13.2). Median PFS was 4.0 months (95% CI, 3.6-6.9), and median OS was 20.9 months (95% CI, 13.7-24.4). The average dose intensity of lenalidomide was 20 mg/day, for a median duration of 94.5 days (range, 1-1,256). Dose reductions or interruptions due to adverse events (AEs) occurred in 40% and 58% of patients, respectively. Neutropenia (44%), thrombocytopenia (28%), and anemia (11%) were the most common treatment-related grade 3/4 AEs. Ki-67 results were available in 81/134 patients, and efficacy data were categorized using 30% and 50% cut-off thresholds for Ki-67 expression (Table 1). Although patient numbers were limited, the ORR was similar in both lower and higher Ki-67 group, but those with lower Ki-67 levels demonstrated better CR rates, DOR and survival outcomes compared with patients with elevated Ki-67. Conclusions Single-agent lenalidomide in heavily pretreated patients with relapsed/refractory MCL post-bortezomib showed durable long-term efficacy with a consistent safety profile. Consistent with what is reported in the literature, high Ki-67 is associated with poor outcome in our cohort with shorter OS. Though based on retrospective evaluation and subsets of patients, the ORR to lenalidomide was similar in both low and high Ki-67 groups, suggesting lenalidomide can be active in patients expressing high levels of Ki67. Prospective studies are needed to confirm these findings. Disclosures: Goy: Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Williams:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Drach:Celgene: Honoraria. Ramchandren:Celgene: Research Funding. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Heise:Celgene: Employment, Equity Ownership. Witzig:Celgene: Research Funding.

Abstract Abstract 1159 Background. Heparin induced thrombocytopenia (HIT) is an immune disorder where platelets are activated by antibodies to a complex of platelet factor 4 antigen and heparin (PF4/H), leading to thrombocytopenia (HIT) and, potentially, thrombosis (HITT). Documentation of anti-PF4/H antibodies in addition to the appropriate clinical findings is essential for making a diagnosis of HIT. In the post-cardiac bypass surgery setting, however, the frequency of elevated anti-PF4/H antibodies is high, whereas the frequency of clinical HIT or HITT is relatively uncommon. Several studies have shown that the presence of anti-PF4/H antibodies may be associated with an increased frequency of adverse outcomes, even in the absence of clinical HIT. The primary objective of this study was to determine the relationship between a positive PF4/H antibody in the postoperative setting with adverse thromboembolic events occurring up to 3 months after cardiac surgery. Methods. Patients undergoing cardiac surgery who were not going to be treated with chronic anticoagulation postoperatively were eligible for this multi-center prospective cohort study. Data were collected daily during hospitalization, and then at 30 and 90 days after surgery using a structured interview format with a standardized questionnaire that included all thrombotic as well as hemorrhagic events, platelet counts, and utilization of antithrombotics in the postoperative setting. The primary outcome variable was a composite endpoint comprising arterial and venous thrombotic events and other miscellaneous events compatible with HIT, as well as death attributable to an event compatible with HIT. Citrated plasma was collected at baseline, pre-discharge (∼4–5 days after surgery), and the 30 day follow-up visit, processed, and stored at −80°C for testing. Laboratory analyses included an anti-PF4/H antibody ELISA (GTI, Waukesha, WI) on all samples, a high-heparin confirmatory test on samples with an OD reading >0.40, and a serotonin release assay (SRA) on all postoperative samples with an OD reading >0.40. A sample size of 800 patients was estimated in order to detect a 3% difference in thromboembolic events assuming a 2 to 10-fold increase risk attributable to seropositivity. Chi-squared testing was used to test the relationship between the primary outcome and postoperative anti-PF4/H levels. Results. Informed consent was obtained from 1030 eligible patients between August 2006 and May 2009, and laboratory and follow-up data were analyzable for 1016 patients. Thirty-day antibody data were available for 888 patients, and fully complete laboratory and 90-day follow-up data were available for 815 patients. The average age was 62 ± 12 years, and 73% of participants were male. A total of 769 patients underwent coronary artery bypass grafting and 237 underwent valve repair or replacement. During the entire study period, there were 17 (1.7%) deaths, 46 thromboembolic events in 44 patients (4.3%), and 25 hemorrhagic events in 24 patients (2.4%). Using an OD cutoff of 0.40 for the ELISA, 339 patients (33.4%) were positive for anti-PF4/H antibodies at the time of discharge, and 630 patients (62%) were positive by day 30. There was no correlation between seropositivity for anti-PF4/H antibodies at the day of discharge or at day 30 and the primary outcome (p=0.47 and 0.73, respectively). Incorporating the high-heparin confirmatory step did not improve the relationship between positive antibody results and the primary outcome. Using a higher cut-off value for the anti-PF4/H antibody ELISA of 1.0 decreased the number of patients with positive results (96 patients at the time of discharge [9.4%] and 221 patients at the 30-day follow-up visit [21.8%]), but this did not improve the relationship between antibody positivity at the day of discharge or day 30 and the primary clinical endpoint, since most patients with the primary endpoint had an ELISA OD below 1.0 (75th percentile of 0.90; 90th percentile of 1.22). Similarly, using the SRA did not identify a relationship between assay results and outcome. Conclusions. The presence of anti-PF4/H antibodies in the postoperative setting following cardiac bypass surgery is not associated with an increased risk for thromboembolic complications. Positive anti-PF4/H results in this clinical setting should be interpreted with caution and only in the context of clinical suspicion for HIT. Disclosures: Ortel: Instrumentation Laboratory: Consultancy; Eisai: Research Funding; GSK: Research Funding. Welsby:CSL Behring: Speaker; CSL Behring: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Principal Investigator. Heit:Daiichi Sankyo: Honoraria; Ortho-McNeil Janssen: Honoraria; Covidien: Honoraria.

Abstract MDS with chromosome 5q deletion [del(5q)] is uniquely sensitive to clonal suppression by lenalidomide (LEN), yielding high rates of cytogenetic and erythroid response. Although haploinsufficiency for a candidate tumor suppressor gene within the common deleted segment (CDS) has been implicated in the pathogenesis of del(5q) MDS, no specific gene products account for the karyotype-dependent LEN sensitivity. Using primary AML cells, we showed that LEN is selectively cytotoxic to del(5q) cells, inducing cell cycle arrest at the G2 > G1 junctures and apoptosis in a concentration-dependent fashion. Now we show that the CDS-encoded Cdc25C and PP2A phosphatases (PPTs) serve as molecular targets for LEN. Cdc25C and PP2A are dual specificity PPTs that regulate cell cycle. The genes encoding the catalytic subunit alpha (PP2ACa), the dominant catalytic isoform, and the regulatory subunit B (beta isoform PR 52) of the PP2A holoenzyme reside within the del(5q) CDS. Real-time RT-PCR showed that Cdc25C and PP2ACa gene expression is significantly reduced in primary del(5q) AML and MDS BM-MNC compared to non-del5q and normal controls. A Cdc25C FISH probe confirmed presence of only a single allele in del(5q) specimens [n=5] vs. normal karyotype [n=5] with no overlap with the EGR1 locus. We found that LEN inhibited rHu-Cdc25C activity with IC90 inhibitory concentrations ≤10nM. Similarly, PP2A PPT activity was inhibited by LEN in enzyme immunoprecipitates from Ramos cells at sub-micromolar concentrations. In U937 cells, we confirmed intracellular Cdc25C and PP2A inhibition, showing concentration-dependent retention of the inhibitory p-Tyr15 -Cdc2 substrates for Cdc25C with corresponding phosphorylation of the PP2A substrate Ser216 Cdc25C, findings reproduced by treatment with the PP2A selective antagonist, fostreicin. Cdc25C immunoprecipitation showed that phosphorylation of Ser216 Cdc25C increased binding to the 14-3-3 protein with consequent cytoplasmic sequestration confirmed by fluorescence microscopy. Phosphorylation of histone H2A.X Ser139 was unchanged after LEN treatment, indicating that phosphorylation of the inhibitory Cdc25C serine does not arise from upstream DNA damage activated kinases. Importantly, siRNA suppression of Cdc25C gene expression in U937 cells promoted LEN-specific apoptosis in 45% of cells, which increased to 68% after fostreicin inhibition of PP2A. These data indicate that haplodeficiency for the Cdc25C and PP2ACa genes promotes selective sensitivity of del(5q) cells to LEN-induced apoptosis. Haplodeficiency of critical drug-able targets may represent a novel strategy for tumor selective therapy.

Abstract Abstract 3816 Background: The hypomethylating agent (HMA) azacitidine (AZA) significantly improves survival compared to conventional care regimens for patients (pts) with “higher risk” MDS (including both Int-2 & High-Risk according to IPSS) (Lancet Oncol 10:223, 2009 – first presented Dec 2007); a more recent trial of the HMA decitabine (DEC) vs. best supportive care in pts with similar IPSS failed to show a significant survival advantage (JCO 29:1987, 2011 – first presented Dec 2008). Since 2006 the immunomodulatory drug lenalidomide (LEN) has been FDA-approved for treatment of anemia in lower-risk MDS pts & deletion of chromosome 5q (Del5q). However, no phase III survival data have been presented with LEN in patients with higher risk MDS, nor is it an expert consensus 1st-line treatment recommendation in higher risk setting (NCCN Guidelines 2011). We sought to evaluate the change in 1st-line treatment preference with these 3 approved agents for higher risk MDS among AHOP's from 2006–2010 in relation to pertinent survival data as it became available. Methods: Between 2006–10 we studied time dependent prescribing preferences of n=1960 AHOP's in a prospective annual research series. Approx. 330–450 individual AHOP's participated in any given year. AHOP demographic data was available from 2007–10 (n=1510); they were predominantly male (77%), working in Community setting (79% vs. 21% Academic), & in small group practice (≤5 providers −59%, including 18% “solo practice”). All regions were represented (NE 23%; SE 22%; Central 19%; SW 13%; West 23%). Most (57%) were >10yrs out from training, and only 18% were <5yrs out from training. A total sample was studied using an extensively tested, live, case-based, market research vehicle to anonymously acquire data. AHOP's were presented with a scenario of an older pt with higher risk MDS (High-Risk 2006–09; Int-2 in 2010) & specific cytogenetic abnormalities, then indicated their preferred treatment from up to 10 relevant available/emerging 1st-line therapeutic options. In each, the scenario was of a pt age 63 yrs (2006–08) or 68–70 yrs (2009–10); with symptomatic anemia & pancytopenia; no response to darbepoietin; with RAEB-2 - excess Bone Marrow blasts 11% (2006–09) to 16% (2010); complex (2006–09) or normal cytogenetics (2010); and both without and then with Del5q in same scenario (2008–10). The distribution of treatment choices was compared over time & according to Del5q status using a chi-square test. Results are shown in Table below. In NON-Del5q scenario, a clear & significant shift toward greater AZA preference by almost 2-fold (from 40% to 78%) was apparent after 2007 (P<0.0001). For same scenario With Del5q (2008–2010), treatment preferences changed significantly over time (P<0.0001), with lower 1st-line AZA and greater DEC & LEN preference (the latter >40% after 2008). In addition, a marked and significant increase in 1st-line LEN preference was observed when AHOP's were presented with the same higher-risk scenario each yr but With-Del5q vs. NON-Del5q (p<0.0001). For “Non Del 5q” vs. “With Del 5q” scenarios, p-values result from a chi-square test, testing for any difference in the distribution of treatment choices over time. *(p<0.0001) - LEN With-Del5q vs. NON-Del5q in higher-risk scenario each year, 2008–2010. Conclusions: Significant changes in 1st-line treatment preferences of AHOPs for pts with higher-risk MDS are apparent in the findings from 2008–10, the time frame following the availability of randomized phase III data demonstrating a survival advantage for AZA therapy. When the presence of a Del5q abnormality is added to the same higher-risk scenario, treatment preferences change dramatically with a significantly increased preference for LEN (despite no available ph III survival data supporting this approach) and for DEC (despite a “negative” ph III trial). These findings suggest important educational gaps concerning the available phase III survival data supporting first line prescribing preferences for patients with higher risk MDS. Efforts to address this gap via evidence-based approaches are warranted. Disclosures: Foran: Celgene: Honoraria; Xcenda: Honoraria. Williams:Xcenda: Honoraria; Celgene: Consultancy, Honoraria, Independent DSMB member, Research Funding. Willey:Xcenda: Employment; Celgene: Business relationship; Eisai: Business relationship. Green:Xcenda: Employment; Celgene: Business relationship; independent DSMB; Eisai: Business relationship.

Abstract Background: International Working Group (IWG) has set criteria in 2003 for response assessment in patients with AML; at which time intensive chemotherapy was the main therapy (Cheson, JCO 2003). Hypomethylating agents (HMA) were approved shortly after for the treatment of elderly AML (Fenaux, JCO 2009; Dombret et al Blood 2015). Although few patients achieve a deep response, the majority will have stable disease (SD), some of which could last several months while patients continue to receive HMA and gain clinical benefit. We hereby describe outcomes for patients who achieve SD with HMA for the treatment of elderly unfit AML patients. Methods: A total of 56 AML patients' data from Feb 2007 to June 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our institution. Patients were considered for our study if they received HMA as frontline therapy for their AML. Patients who received HMAs after induction chemotherapy failure or for their MDS were excluded. Response was identified based on 2003 IWG AML response criteria. Patients with SD were categorized into short-lasting (<6 cycles of HMA, cohort 1) or long-lasting (≥6 cycles of HMA, cohort 2) SD.Prognostic factors were analyzed by univariate and multivariate analyses. Survival estimates were calculated using Kaplan-Meier curves and univariate and multivariate analyses was based on log-rank testing using JMP software version 10. Results: i) Characteristics: Fifty six AML patients were treated with HMA as frontline therapy with median age of 76 years (range, 59-91), 68% of which were males. Therapy related AML (T-AML) was seen in 2% of the cases. Cytogenetics were favorable risk in 2%, intermediate in 62%, and poor in 36%. Complete remission (CR) was found in 10 (18%) patients, CR with incomplete count recovery in 3 (5%), partial remission (PR) in 3 (5%) patients. Forty patients were non-responders (SD). ii) Characteristics of HMA SD cohorts: Upon comparison of cohort 1 versus cohort 2 there was no statistical significance in median age, white blood count, absolute neutrophil count, platelets, peripheral blood and bone marrow blasts, bone marrow cellularity and sex. Median number of cycles was expectedly higher in cohort 2 vs 1 (9 vs 2, p<0.0001). Intermediate cytogenetic risk was more common in cohort 2 vs 1 (90% vs 43%, p=0.006), while poor risk was more common in cohort 1 vs 2 (57% vs 10%, p=0.006). Only 10% had complex karyotype in cohort 2 compared to 50% in cohort 1 (p=0.017). NPM1 mutation was absent in all cases, while FLT3 mutation was present 30% in cohort 1 and 25% in cohort 2 (p = 0.9). Decitabine was more commonly given in cohort 1 vs cohort 2 (80% vs 50%, p =0.07). iii) Clinical outcome of HMA SD cohorts : Median overall survival was higher in long-lasting SD patients (cohort 2) vs short-lasting SD (18 vs 4 months, p = 0.0002). Upon multivariate analysis, both age (p <0.0001) and long-lasting SD (p =0.01) were statistically significant for overall survival but not cytogenetics risk grouping nor type of HMA administered. Conclusions: Standard response criteria for AML by IWG were developed for intensive chemotherapy and do not apply to newer agents, specifically HMA. Stable disease (SD) could be meaningful to some elderly AML patients when treated with HMA. Intermediate cytogenetics and azacitidine use were more frequent in patients with long-lasting SD. Long-lasting SD did confer a survival benefit in elderly AML patients. Newer response criteria for assessing novel agents' efficacy are needed in this population. Figure Figure. Disclosures Tibes: Italfarmaco S.p.A.: Consultancy, Honoraria. Foran:pfizer: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; medscape: Honoraria; karyopharm: Honoraria; novartis: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Al-Kali:Novartis: Research Funding; Celgene: Research Funding.

Abstract 44 patients with relapsed or refractory CD20+ NHL were enrolled on a phase I trial of dose-escalated 90YZ followed by high-dose BEAM and autotransplant in which the 90YZ dose was patient-specific based on dosimetry. 90YZ doses were calculated to deliver cohort-defined radiation doses (100–1700 cGy) to critical organs (liver, lung or kidney) with 3–6 patients per cohort. On D-22, rituximab (R) 250 mg/m2 was infused followed by 111In Zevalin®. Imaging was performed immediately and at 4, 24, 72 and 144 hours; dosimetry was performed on D-15. On D-14, R was followed immediately by 90YZ at the cohort-prescribed dose. On D-6 through D-1, patients received high-dose BEAM. On D0, a minimum of 2.0 × 106 CD 34+ cells/kg was infused and G-CSF 5 μg/kg SQ daily begun. The median age was 54 (range: 25–73) years. NHL histologic subtypes were as follows: 16% mantle cell, 57% diffuse aggressive, 11% low-grade and 16% transformed. 43% had recieved 3 or more chemotherapy regimens, and 70% had received R either alone or in combination with chemotherapy. The toxicity profile was similar to that associated with high-dose BEAM. The most common grade III/IV toxicities were infection, fever, stomatitis, nausea, vomiting, diarrhea. One patient experienced transient veno-occlusive disease at the 700 cGy dose level. Two dose-limiting toxicities occurred at the 1700 cGy dose level: one patient with grade 4 stomatitis died of pneumonia and sepsis on D+10, and one patient experienced septic emboli to the lung on D+13. Engraftment occurred at a median of 10 days (range: 8–18 ) to granulocytes ≥ 500/μL, and 21 days (range: 11–40 days) to platelets ≥20,000/μL. One heavily pretreated patient developed MDS on D+291 and expired of sepsis on D+483. With a median follow-up of 21 months, the three year overall and progression-free survivals are 52% and 37%, respectively. 90YZ Zevalin ® Dosing for Cohorts 5–9 (median;range) Cohort (cGy) Total Dose (mCi) mCi/kg 900(n=3) 28(27–37) 0.3(0.3–0.4) 1100(n=5) 51(29–65) 0.6(0.5–0.8) 1300(n=5) 61(39–98) 0.6(0.5–1.1) 1500(n=6) 73(51–99) 0.9(0.5–1.4) 1700(n=3) 98(82–104) 1.2(1.1–1.2) For dosimetry-based trials, 1500 cGy to the critical organ (nearly always liver) is the recommended dose. Although patient-specific doses calculated to deliver a cohort-prescribed absorbed radiation dose to the critical organ were highly variable, the two dose-limiting toxicities ocurred at nearly identical doses (1.14, 1.20 mCi/kg) when calculated according to weight. Whereas eight other patients safely received at least twice the conventional 0.4 mCi/kg dose, 0.8 mCi/kg is the recommended dose for phase II studies, if dosing is to be based on weight and not dosimetry. Outcomes are encouraging given the high-risk patient population. A phase III trial will be required to establish whether or not the addition of 90YZ to high-dose BEAM improves outcomes in NHL patients undergoing autotransplant.