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Since November 1996, CNA has participated on a Technology Task Force established by the Commander, Navy Recruiting Command, to address several issues concerning the use of technology and Navy recruiting. This annotated briefing summarizes our ongoing efforts in three areas: Internet recruiting, Intranet showcase, and interactive multimedia. The unifying theme to these topics is the need for Navy recruiting to keep up with the rapid changes occurring in marketing and the exchange of information. High-tech methods of marketing and processing applicants should be pursued in order r to keep pace with the tremendous changes in the marketplace.

SummaryExperiments were undertaken to develop intracytoplasmic sperm injection (ICSI) to produce caprine embryos out of the normal breeding season. Oocytes were obtained from 2–6 mm ovarian follicles at slaughter. Selected oocytes with two to four layers of cumulus cells were incubated in 1 ml of H-TCM 199 supplemented with 10 μg each of oFSH and bLH (NHPP, NIDDK, NICHD, USDA) and 20% fetal bovine serum (FBS) in a thermos (38.5°C) for 4.5 h during transportation. Then, oocytes were transferred into 75 μl of freshly prepared maturation medium under paraffin oil and a mixture of 5% O2, 5% CO2 and 90% N2. Approximately 26 h after recovery oocytes were denuded by incubation with hyaluronidase (100 IU/ml) and pipetting and held at 38.5°C for 90 min. Spermatozoa frozen in egg yolk extender were thawed in a 37°C water bath for 15s. Motile fractions were selected by swim-up, then incubated for 90 mm in TALP with 10 μg heparin/ml. Each oocyte was positioned with its first polar body at 6 or 12 o'clock by a holding pipette. Sperm (1 μl) were added to 10 μl medium containing 10% polyvinylpyrrolidone. A sperm cell was aspirated into a pipette, and then injected head-first into the cytoplasm of an oocyte maintained in H-TCM 199 + 20% FBS at 37°C. Injected oocytes were transferred to HM and, after 90 min, cultured in 50 μl of BSA-free synthetic oviduct fluid plus polyvinyl alcohol, citrate and non-essential amino acids. Results demonstrate that caprine blastocysts can be produced outside the breeding season by the use of frozen-thawed semen and injection of sperm cells with broken tails into ova followed by culture in defined medium.

HBM ESD tests on two types of 0.6μm DRAM devices showed that internal circuit or output driver failures would occur after the input or I/O pins were ESD stressed negative with respect to Vcc at ground. These failures occurred at lower than expected ESD stress voltages due to power-up circuit interactions that either turned-on unique internal parasitic ESD current paths or disrupted the normal operation of the output pin's ESD protection circuit. ESD analysis found there exists a set of power-up sensitive circuits and if placed near a Vcc bond pad can result in low voltage ESD failures.

PROBLEM: Are the effects of ruminant trophoblast interferon-tau (IFN-τ) on uterine prostaglandin (PG) secretion a specific action of this cytokine and what are the effects of IFN-τ on expression of uterine genes not generally associated with pregnancy maintenance? METHODS: The effects of IFN-τ and IFN-α on bovine uterine explant and epithelial cell production of PGF 2α and PGE 2 were determined in the presence and absence of oxytocin (OT). The effects of intrauterine administration of IFN-T were determined on uterine expression of retinol-binding protein (RBP) and transforming growth factor-beta (TGF-β) isoforms. RESULTS: IFN-τ attenuated uterine endometrial secretion of PGF 2α and PGE 2 in vitro and diminish PG stimulation by OT. IFN-τ and IFN-α were observed to be equipotent. Intrauterine infusion of IFN-τ resulted in a significant decrease in steady-state RBP mRNA levels and expression of TGF-B1,2, and 3 mRNA levels were lowest in IFN-τ treated animals. CONCLUSION: Negative regulation of gene expression may be a general strategy in IFN activity. This may explain the similar activities of IFN-τ and IFN-α on a broad variety of cell types, including ruminant uterine endometrium.

Background DHL are high-grade B-cell lymphomas (BCL) characterized by dual gene rearrangements (RA) of MYC and either BCL2 or BCL6. Outcomes are typically dismal, particularly when treated with R-CHOP, as compared to those observed in patients (pts) with similar histologies without dual RA. Few reports have evaluated the use of intensive induction regimens, with or without consolidative stem cell transplantation (SCT). We sought to evaluate the role of intensive induction as well as SCT, and to investigate predictors of outcome in DHL. Methods This study was an IRB-approved retrospective analysis across 15 centers. Cases were diagnosed between 2000-2012 as aggressive BCL harboring RA, by FISH, of MYC along with RA of BCL2 and/or BCL6. Pts were treated with either R-CHOP, or one of the following intensified regimens: R-HyperCVAD, R-EPOCH, R-CODOX-M/IVAC, R-ICE. Survival was estimated using Kaplan Meier method, and comparisons made with log rank test. Multivariable analysis (MVA) was performed using the Cox proportional hazard regression. Results One hundred six pts were analyzed. Median age at diagnosis was 60; 59% were male. The majority had DHL characterized by RA of MYC and BCL2 (77%); the remainder showed RA of MYC and BCL6 (10%), or all three (12%). History of indolent lymphoma was present in 29 pts (27%). The most common histology was DLBCL in 56 pts (53%), followed by BCL unclassifiable (BCLU) in 45 (42%), and Burkitt-like in 5 (5%). Thirty six pts (33%) received R-CHOP, 33 (31%) R-EPOCH, and 28 (36%) R-Hyper-CVAD or CODOX-M/IVAC. Fourteen pts (13%) were consolidated with SCT (n=1 allo and n=13 auto SCT); all were treated with intensive induction. Three additional pts underwent SCT in partial remission or progressive disease following R-CHOP induction. The median PFS and OS for the entire cohort were 8.8 mo and 12 mo, respectively (Table 1); of the 24 pts (23%) alive and without progression, median follow-up was 19 mo. R-EPOCH was superior in achieving complete response (CR) compared with R-CHOP (P 0.01), and trended towards significance compared with pts receiving other intensive induction (P 0.07). Additionally, primary refractory disease, observed in 37 pts (34.5%), occurred less frequently in pts receiving R-EPOCH compared to R-CHOP (P .005) or other intensive regimens (P 0.03); induction regimen did not impact OS in patients not receiving SCT (P 0.7; Fig 1). SCT in first remission was associated with improved OS (P 0.02), and PFS (P 0.006) compared with induction alone. However, among pts achieving CR, SCT was not associated with improved OS compared with observation (P 0.22; Fig 2). Pts with prior history of indolent NHL did not fare worse than those with de novo DHL (P 0.5). No difference in OS was observed based on histology (P 0.2). The following factors were evaluated in MVA: prior indolent lymphoma, histological subtype, IPI>/=3, primary refractory disease, type of induction (R-CHOP vs intensified), and consolidative SCT. Only primary refractory disease (P Conclusions In this analysis of DHL, primary refractory disease was the primary predictor of OS. Pts achieving CR did not appear to benefit from consolidative SCT, though our analysis was limited by the fact that pts receiving SCT are often highly selected (for chemosensitivity, age, comorbidities) and in this study, by the low number of pts receiving SCT. R-EPOCH was associated with a decreased rate of primary refractory disease compared to other regimens, and increased rate of CR compared to R-CHOP, but the lack of clear survival benefit suggests that relapsed disease offsets early benefit. Our analysis confirms the generally poor outcomes for pts with DHL, though a subset with chemosensitive disease has an improved prognosis, likely due to favorable disease biology. Further investigation on the role of SCT and of novel agents is needed for this high-risk population. ^Three patients untreated, one received multiple regimens Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Petrich:Genetech: Consultancy, Honoraria. Fenske:Seattle Genetics : Consultancy, Honoraria. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Evens:Seattle Genetics: Consultancy, Honoraria; Millennium: Consultancy, Honoraria, Research Funding; Ziopharm, Inc: Research Funding; Celgene: Consultancy, Honoraria.

Background Progression free and overall survival (PFS/OS) for Multiple Myeloma (MM) have improved over the past 20 years largely as a result of ASCT as well as novel conventional dose therapeutic agents. However, since the 1990s improvements in PFS and OS due to ASCT have improved minimally due to continued reliance on single agent melphalan (MEL). In order to improve PFS and OS, better transplant regimens should be investigated. The combination of Busulfan (BU) and MEL delivers better PFS compared to MEL alone (Lahuerta, et al) with similar toxicity rates to MEL alone. Furthermore, in vitro and in vivo studies indicate synergy between MEL and proteasome inhibitors such as Botezomib (BTZ). Superior response rates and PFS were seen when BTZ is combined with MEL when compared with historical controls using MEL in a recent IFM study. (Roussel et al. Blood 2010). We hypothesize that IV BU and MEL followed by BTZ (BuMelVel) could be an effective preparative regimen with acceptable toxicity for patients with MM. Methods Between July 2009 and June 2013 57 patients with Multiple Myeloma who had already undergone induction therapy and were eligible for ASCT were enrolled. Patients received IV BU administered as a daily intravenous infusion for a total of 4 days with the first 2 days (day -6, -5) at fixed dose of 130 mg/m2 over 3 hours and the subsequent 2 doses (day -4, -3) adjusted to achieve a target area under the concentration-time curve (AUC) total of 20,000 mM* min. Pharmacokinetic (PK) analysis performed after the first dose of IV Bu was used to determine Bu AUC and individualized Bu PK-directed dosing for later doses (d-4 and -3). MEL was administered at 140 mg/ m2 IV over 15-30 minutes on D-2. BTZ 1.6 mg/m2 was administered IV push on D-1. Palifermin was given for mucoprotection at a dose of 6.25 mg IV for two consecutive days before the first busulfan dose (days -8 and -7). A third dose of 6.25 mg was give on day 0 after stem cell transplantation. Results Of the 57 patients enrolled 56 are evaluable for toxicity and 54 for response at D +100. Median age is 61 (31 - 72). 49 % of patients had received ≥ 2 induction regimens (range 1-4) and 69% were DS stage III. 38% of patients had achieved at least a VGPR after induction with 9% of those achieving a CR. After transplantation, 70% of patients had at least a VGPR including 37% CR or sCR. All but 4 patients had a PR or better to induction therapy (three had stable and one progressive disease). The most common grade ≥ 3 toxicities were neutropenic fever (n = 42) and mucositis (n=21). No VOD or treatment related deaths at D+100 were observed and all patients engrafted. Median time to engraftment was 10 days (range 10-12) and median hospital stay was 20 days ( 15-31). Median PFS at 2 years was 78%. Conclusion BuMelVel is an effective novel preparative regimen with ≥ VGPR and CR/sCR of 70% and 37% respectively which compare favorably to responses previously reported with MEL 200 alone (43% and 11%, respectively) by Roussel et al. At the time of reporting, 12 patients had relapsed; 2 and 3-year PFS rates were 78% and 60% respectively. The regimen of BuMelVel is well tolerated and may lead to improvements in PFS and OS in patients with multiple myeloma. Disclosures: Rodriguez: Otsuka: Research Funding; Millennium: Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau.

Background Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The standard of care for patients (pts) with relapsed or refractory HL is salvage chemotherapy followed by autologous stem cell transplant (auto-SCT). However, approximately 50% of pts experience relapse of HL after auto-SCT and this population represents a pronounced unmet need. In a 756-pt retrospective analysis, the median overall survival (OS) in HL pts who relapsed after auto-SCT was 2.4 years, as measured from the time of auto-SCT, with shorter time to relapse after auto-SCT being the most predictive factor for shortened survival (Arai 2013). Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. A pivotal phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in 102 pts with relapsed or refractory HL after auto-SCT (ClinicalTrials.gov #NCT00848926). Data representing approximately 3 years of follow up from this ongoing trial are described, including characterization of patients who experienced long-term remissions. Methods Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Long-term follow-up assessments to determine survival and disease status occurred every 3 months (mos) for 2 years, every 6 mos during years 3 to 5, and annually thereafter. Results In this high-risk population with poor prognosis, the median time to relapse after auto-SCT was 6.7 mos (range, 0–131 mos). Pts received a median of 9 cycles of brentuximab vedotin and the ORR was 75% (76 of 102 pts), with complete remissions (CRs) in 33% of pts (n=34). As previously reported, the most common (≥15%) brentuximab vedotin-related adverse events of any grade were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of Grade 3 or higher that occurred in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. At the time of this analysis (May 2013), the median observation time from first dose was 32.7 mos (range, 1.8 to 48.3 mos). Of the 102 pts enrolled, 51 (50%) were alive at the time of last follow up. The median OS was 40.5 mos (95% CI: 28.7, – [range, 1.8 to 48.3+ mos]) and the estimated 36-mo survival rate was 54% (95% CI: 44%, 64%). Median OS by best clinical response was CR (n=34): median not yet reached; partial remission (PR, n=42): 31.6 mos; stable disease (SD, n=22): 20.6 mos; and progressive disease (PD, n=3): 10.2 mos. Of the 51 pts who were alive at the time of this analysis, 14 remain in remission and have not started a new anti-cancer therapy other than 5 pts who received consolidative allo-SCT following brentuximab vedotin. Demographics/baseline characteristics of these 14 pts show that the majority are female (10/14; 71%) and white (12/14; 86%), with a median age of 26.5 years (range, 15–54). Eleven of the 14 pts had CRs and 3 had PRs following brentuximab vedotin; all 3 of the pts with PRs received subsequent allo-SCT. The observation time for the 14 pts who remain in remission ranges from 31.5 mos to 44.4 mos and their progression-free survival ranges from 27.2+ mos to 44.4+ mos. Additional characterization of the pts who achieved long-term remissions following brentuximab vedotin will be presented at the meeting. Conclusions After a median observation time of approximately 3 years from first dose of brentuximab vedotin, 50% of pts with relapsed or refractory HL were alive at the time of last follow up. The median OS was 40.5 mos. Fourteen patients remain in follow up with no evidence of lymphoma progression, providing early suggestion that a fraction of these patients may be cured. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with AVD (doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for frontline treatment of HL (ClinicalTrials.gov #NCT01712490). Disclosures: Gopal: Biogen, Idec: Research Funding; Merck: Research Funding; BioMarin: Research Funding; Gilead: Research Funding; Emergent/Abbott: Research Funding; Pfizer: Research Funding; Cephalon/Teva: Research Funding; Janssen: Research Funding; Millennium: Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; Piramal: Research Funding; Spectrum: Research Funding. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Trave expenses Other. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Ansell:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding; University of Miami: Employment. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria. Larsen:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda Cambridge US: Employment; Takeda: Equity Ownership. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding; Sanofi-Aventis: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Incyte: Honoraria; Millennium: Honoraria; Pharmacyclics: Honoraria; Curis: Honoraria; Genentech: Research Funding; Gilead: Research Funding; Johnson and Johnson: Research Funding; Infinity: Research Funding.

Introduction Non-Hodgkin’s Lymphoma (NHL) is the most common hematologic malignancy in the United States with 69,700 new cases and 19,000 deaths predicted in 2013. The majority of patients diagnosed with NHL respond well to conventional chemotherapy, however, patients with relapsed or refractory NHL usually have poor long-term outcomes. While autologous stem cell transplantation (auto-SCT) is a mainstay for patients with relapsed or refractory disease that are chemotherapy-sensitive, allogeneic stem cell transplantation (allo-SCT) has been used to treat NHL in patients who have relapsed after auto-SCT, are chemotherapy-resistant, or have adverse risk factors. While some evidence has suggested that chemotherapy-resistant disease status prior to allo-SCT is associated with a poor prognosis, limited data exists to guide evidence-based transplant paradigms. We sought to determine if disease status prior to allo-SCT in patients with relapsed or refractory NHL impacts outcomes. Methods A retrospective chart review identified 154 patients diagnosed with relapsed or refractory NHL who underwent an allo-SCT at Loyola University Medical Center between January 1998 and January 2012. Fifteen patients were excluded for lack of data yielding 139 patients over a 14-year period. Of our patients with relapsed or refractory disease, chemotherapy-sensitive patients were defined as patients with partial or complete response to chemotherapy at time of transplant. Chemotherapy-resistant patients were defined as patients that either had progressive disease or were refractory to chemotherapy at time of transplant. Data on age, sex, type of NHL, stage at diagnosis, chemotherapy regiment, previous auto-SCT, disease status prior to allo-SCT, overall survival, and cause of death were collected. Results Of the 139 patients, the median age was 48 years with a male to female ratio of 1.4:1. The majority of patients had stage 3 or 4 disease (74%). Breakdown of NHL subtype revealed 31% diffuse large B-cell (DLBCL), 31% follicular, 13.7% mantle cell, 8% T-cell, 3.6% Burkitt’s, 2.1% marginal cell, and 10.7% other category that included small lymphocytic, anaplastic, natural killer cell, mixed cellularity, and unspecified NHL. A total of 44 patients (31%) underwent auto-SCT prior to allo-SCT. Subtypes of allo-SCT included matched sibling (45.3%), matched unrelated donor (MUD, 39.6%), and cord blood transplant (15.1%). Matched sibling allo-SCT had an improved 2 year overall survival of 57.1% when compared to MUD and cord allo-SCT (33% and 30%, respectively). Overall survival after allo-SCT for all patients was 41% at 3 years and 33.1% at 5 years. Disease status prior to transplant was divided into two categories: (1) chemotherapy-resistant (97 patients, 69.7%) and (2) chemotherapy-sensitive (42 patients, 30.2%). There was no statistical difference in overall survival between the chemotherapy-resistant and chemotherapy-sensitive groups at 6 months (60.8% and 78.5% respectively, p=0.066) and at 3 years (40.2% and 42.8% respectively, p=0.91). In a subgroup analysis, DLBCL patients with chemotherapy-resistant disease had similar 3 year survival as compared to patients with chemotherapy-sensitive disease (22.2% and 23%, respectively, p=0.93). Similar results were observed for both subgroups of patients with follicular lymphoma, with 55.2% survival in the chemotherapy-resistant group as compared to 64.2% in the chemotherapy-sensitive group at 3 years (p=0.81). Conclusion Our data suggest that disease status at the time of transplant does not impact survival outcomes in patients with relapsed or refractory NHL. This finding extended into a sub-group analysis of DLBCL, representative of an aggressive NHL subtype, and follicular cell lymphoma, representative of an indolent NHL subtype. We hypothesize that the comparable survival outcomes between chemotherapy-sensitive and chemotherapy-resistant disease states at transplant may be a result of graft versus lymphoma effect and use of a disease free graft. As no survival advantage was incurred in patients with chemotherapy sensitive disease, these data imply that the lymphoma burden at time of transplant is not prognostic. This potentially highlights the utility of earlier time to transplant in patients with chemotherapy-resistant disease, and perhaps suggest limiting the duration of attempted salvage chemotherapy after disease relapse. Disclosures: No relevant conflicts of interest to declare.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin’s lymphoma (NHL) characterized by the chromosomal translocation t (11;14) (q13;q32). It comprises approximately 6% of all NHL, but has a highly aggressive clinical course. While 60-90% of patients achieve complete remission (CR) with augmented induction regimens, approximately 85% will eventually relapse with a median overall survival (OS) of 3-4 years with less than 15% of patients alive at 5 years. Optimal initial therapy for this disease usually includes for those in first CR autologous hematopoietic stem cell transplant (HSCT), with allogeneic HSCT reserved for those who relapse. Patients who are non-responsive to first-line chemotherapy are increasingly being considered for an allogeneic HSCT. Methods After obtaining IRB approval, a retrospective chart review was performed on all patients with a diagnosis of MCL (confirmed by histology) at LUMC to compare the outcome of transplants vs. non-transplants patients. Primary end points were overall survival (OS) and progression-free survival (PFS) after stem cell transplant. A total of 104 patients were evaluated from 1999 to 2013, of whom 63 underwent a transplant after induction therapy and 13 an allograft after first relapse. Results The induction chemotherapy regimens used for the 104 patients were CHOP(R) in approximately 50% and Hyper-CVAD in 25%. A total of 51 patients received a first remission autologous HSCT, of these 20 patients were in CR1 at the time of transplant. A total of 25 patients received an allogeneic transplants (15 were sibling and 10 unrelated grafts); 12 underwent first-line allogeneic transplant with 65% receiving a reduced intensity regimen. In the group of 13 patients who relapsed after autologous HSCT, 90% received a reduced intensity regimen. Survival analysis by treatment modality was as follows: median OS for the non-transplant and transplant cohorts respectively were 29 months and 63.5 months (p=0.007). Median OS was not reached for patient who received first-line allogeneic HSCT while median OS for patient failing a prior autologous HSCT who received an allogeneic transplant was 28 months. Of the 12 patients who underwent first-line allogeneic transplant, despite all having chemo-resistant disease after induction therapy, no patient died of relapse; the only patient who relapsed received bortezomib and rituximab and achieved complete remission. Of the 13 patients who received an allogeneic transplant after prior autologous transplant, only two patients died of relapsed disease but nine patients died of transplant-related complications, largely related to their poor performance status due to multiple chemotherapy regimens associated with their refractory lymphoma. Conclusions Our results for autografts are consistent with the data available in the literature confirming the benefit of this strategy as part of induction treatment. However this analysis suggests a significant benefit for early allografts for those failing induction therapy, presumably due to a potent graft vs. lymphoma effect despite chemotherapy resistance. Such an effect also occurs for allografts performed after autograft failure, but the frailty of patients does impact its benefit. Based on our data, patients in CR1 should be considered for ASCT after initial therapy, however those in less than CR after initial therapy should be considered for an early allogeneic transplant. Disclosures: No relevant conflicts of interest to declare.

Background Allogeneic hematopoietic stem cell transplantation (HDT) in the elderly patient with acute myeloid leukemia (AML) or myelodysplasia (MDS) continues to pose a challenge due to treatment failure and treatment related toxicity. TBI/Cy, allows for engraftment and tolerance while maximizing anti-tumor activity, but can be a difficult regimen in elderly patients due to its associated toxicity profile. The introduction of reduced intensity conditioning regimens (RIC) and improved supportive care has led to decreased mortality following HDT in the elderly. However, for patients at high risk for relapse, RIC may not achieve prolonged disease control. For these patients, an ablative HDT with reduced toxicity (RT-SCT) may be beneficial by controlling disease with acceptable toxicity while allowing a GVL effect. We evaluated a novel conditioning regimen in an open label phase II study consisting of Bu/Pent aimed at improving toxicity, relapse rate, and overall survival (OS) in elderly patients with AML or MDS, and compared them with an elderly group who received TBI/Cy. Methods We treated 54 patients with AML/MDS over the age of 55, who were recipients of HDT from fully matched related donor (MRD), umbilical cord donor, or matched unrelated donor (MUD). We defined elderly as greater than 55 years of age. The median age in the Bu/Pent group was 64, 61% had adverse prognostic features including cytogenetics, relapsed, treatment related or transformed disease, or high IPSS score, 39% were in the intermediate group. There were 60% MRD and 40% unrelated HDT. In the TBI group median age was 59, 48% had adverse features and 52% intermediate, 48% MRD and 52% unrelated HDT. The Bu/Pent group (n=23) was conditioned with intravenous busulfan 1.6mg/kg every 12 hours day -7 to -4 and pentostatin 4mg/m2 on day -3 and day-2 prior to SCT on day 0. GVHD prophylaxis was methotrexate 10mg/m2 on day 1 and 5mg/m2 on days 3 and 6. Tacrolimus was started on day -2 and tapered over 1 month after day +100. Relapse, survival and toxicity data was compared with a historical control group at our institution who received 12 Gy TBI/Cy (60 mg/kg x 2) (n=31). Controls were selected by retrospective chart review of patients with a diagnosis of MDS or AML who had received an allogeneic transplant with a TBI/Cy based conditioning regimen after the age of 55. There was no graft failure reported in either group. The OS at 100 days and 1-year post HDT was significantly better for the Bu/Pent group vs. TBI group (82.6% vs. 51.6% and 43.5% vs. 25.8% respectively; p value= 0.029). Progression free survival (PFS) was also significantly better in the elderly population receiving Bu/Pent; 43.5% at 1 year versus 22.6% in the TBI group with a p value of .021. The rate of relapse was comparable regardless of conditioning regimen with 34% in the Bu/Pent group (8/23) and 29% in the TBI/Cy group (9/31) relapsing. Transplant related mortality (TRM) accounted for 13% (3/23) of the deaths in the Bu/Pent group, and 38% (12/31) in the TBI/Cy group. Of the three deaths in the Bu/Pent group, 2 were due to GVHD and 1 was secondary to sepsis within 100 days. Other significant nonfatal toxicities such as mucositis and nausea/vomiting were medically managed and rates of GVHD were similar in the two groups; 10/23 (43%) in the Bu/Pent group and 14/31 (45%) in the TBI group. Of the 10 GVHD patients in the Bu/Pent group, 7 had chronic (cGVHD) (30%). None of the patients in the Bu/Pent group and 3/31 in the TBI group developed VOD. Upon sub-group analysis, elderly CIBMTR high-risk AML/MDS patients who received Bu/Pent had an 86% 100 day survival versus 60% in the TBI/Cy group; 1 year survival was 43% and 33% respectively. In the elderly CIBMTR intermediate risk group, Bu/Pent 100 day survival was 78% vs. 44% in the TBI group. At 1 year, patients in the intermediate group who received Bu/Pent had 45% survival vs. 19% in the TBI group. Conclusion We found that OS and PFS at 100 days and 1 year were significantly better in the Bu/Pent group due to a much lower TRM. The Bu/Pent based regimen appears to be superior for patients over the age of 55 with MDS or AML undergoing HDT when compared with TBI based regimens. With a low toxicity profile, Bu/Pent patients had a lower incidence of TRM when compared with a prospective study of patients receiving RIC-SCT busulfan/fludarabine (20%) and a lower incidence of cGVHD(53%) (Valcarcel et al). This regimen warrants further prospective evaluation. p value= 0.029 p value= 0.021 Disclosures: Smith: Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Rodriguez:otsuka: Honoraria, Research Funding.

e19511 Background: Case series to date (Chen and Gopal) have reported safety and efficacy of b. vedotin prior to allo-SCT. We report our experience using b. vedotin prior to allo-SCT. Methods: Patients were treated with b. vedotin through Seattle Genetics trials and identified retrospectively using a registry of b. vedotin use and subsequent allo-HCT. Patients were treated per study protocol and received 1.8 mg/kg b. vedotin administered every 3 weeks for up to 16 cycles. Patients were followed for response, survival/disease status and subsequent therapy. Results: 7 patients were identified with a median of 5.7 prior therapies. Of these patients 5 had HL histology and 2 had ALK+, ALCL histology. The median age was 37.0 years. The median time since initial diagnosis was 60.4 months. All 7 patients had previously received an autologous SCT. Patients with primary refractory disease accounted for 42% of patients. Patients received a median of 8.6 cycles of b. vedotin and 86% of patients achieved an objective response; best response was CR for 3 patients and PR for 3 patients. Median maximum tumor reduction was 43%. Median time from b. vedotin to transplant was 7.6 months. Three patients received additional chemotherapy post b.vedotin and prior to allo-SCT. The PFS and OS are 86% with 6 patients alive and without relapse in follow-up post allo-SCT. There was 1 transplant related death at induction which did not appear related to b. vedotin. The median follow up is 17.5 months. The median time to neutrophil engraftment was 12.3 days. The median time to platelet engraftment was 21.6 days. Their were no episodes of aGVHD and 33% of patients developed cGVHD all Grade I/II. No increase in infections was observed. Conclusions: Treatment with b.vedotin provided significant decrease in tumor volume in patients with relapsed CD30+ lymphoma, and allowed for allo-SCT. There was no evidence of a delay in engraftment, aGVHD, cGVHD, or post transplant infectious complications. Our results add to prior reports that b. vedotin is a safe and effective option for reducing tumor burden to facilitate a potentially curative allo-SCT and warrants further study.

Heparan sulfate proteoglycans and their corresponding binding sites have been suggested to play an important role during the initial attachment of murine blastocysts to uterine epithelium and human trophoblastic cell lines to uterine epithelial cell lines. Previous studies on RL95 cells, a human uterine epithelial cell line, had characterized a single class of cell surface heparin/heparan sulfate (HP/HS)-binding sites. Three major HP/HS-binding peptide fragments were isolated from cell surfaces by tryptic digestion, and partial amino-terminal amino acid sequence for each peptide fragment was obtained (Raboudi, N., Julian, J., Rohde, L. H., and Carson, D. D. (1992) J. Biol. Chem. 267, 11930-11939). In the current study, using approaches of reverse transcription-polymerase chain reaction and cDNA library screening, we have cloned and expressed a novel, cell surface HP/HS-binding protein, named HP/HS interacting protein (HIP), from RL95 cells. The full-length cDNA of HIP encodes a protein of 159 amino acids with a calculated molecular mass of 17,754 Da and pI of 11.75. Transfection of HIP full-length cDNA into NIH-3T3 cells demonstrated cell surface expression and a size similar to that of HIP expressed by human cells. Predicted amino acid sequence indicates that HIP lacks a membrane spanning region and has no consensus sites for glycosylation. Northern blot analysis detected a single transcript of 1.3 kilobases in both total RNA and poly(A+) RNA. Examination of human cell lines and normal tissues using both Northern blot and Western blot analyses revealed that HIP is expressed at different levels in a variety of human cell lines and normal tissues but absent in some cell lines and some cell types of normal tissues examined. HIP has relatively high homology (approximately 80% both at the levels of nucleotide and protein sequence) to a rodent ribosomal protein L29. Thus, members of the L29 family may be displayed on cell surfaces where they may participate in HP/HS binding events.

Abstract 3689 Background: Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The standard of care for patients (pts) with relapsed or refractory HL is salvage chemotherapy followed by autologous stem cell transplant (auto-SCT). However, approximately 50% of pts experience relapse of HL after auto-SCT and this population represents a pronounced unmet need. In a 756-pt retrospective analysis, the median overall survival (OS) in HL pts who relapsed after auto-SCT was 2.4 years, as measured from the time of auto-SCT, with shorter time to relapse after auto-SCT being the most predictive factor for shortened survival (Horning et al, 2008). Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Brentuximab vedotin selectively induces apoptotic death of CD30-positive cells by binding, internalizing, and releasing MMAE. A pivotal phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in 102 pts with relapsed or refractory HL after auto-SCT (ClinicalTrials.gov #NCT00848926). Long-term survival data from this ongoing trial are described. Methods: Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Long-term follow-up assessments to determine survival and disease status occurred every 3 months (mos) for 2 years, every 6 mos during Years 3 to 5, and annually thereafter. Results: In these heavily pretreated pts with poor prognosis, the median time to relapse after auto-SCT was 6.7 mos (range, 0–131 mos). Pts received a median of 9 cycles of brentuximab vedotin and the ORR was 75% (76 of 102 pts), with complete remissions (CRs) obtained by 33% of pts (n=34). At the time of this analysis (July 2012), the median observation time from first dose was 29.5 mos (range, 1.8 to 36.9 mos). 60 of 102 pts (59%) were alive at the time of last follow up and the median OS has not yet been reached. The estimated 24-mo survival rate was 65% (95% CI: 55%, 74%). Median OS by best clinical response was 31.6 mos for pts with partial remission (PR, n=42), 20.6 mos for pts with stable disease (SD, n=22), and 10.2 mos for pts with progressive disease (PD, n=3); median OS for pts who obtained a CR (n=34) has not yet been reached. Evaluation of numerous demographic and baseline characteristics including age, gender, bone marrow involvement, presence of B symptoms, tumor size, and ECOG performance status showed that the only subgroup of pts who had a significantly more favorable survival rate following brentuximab vedotin treatment were those with a baseline ECOG score of 0 (24-mo survival rate of 81% vs. 47% for pts with ECOG scores of 0 vs. 1, respectively). Notably, no significant difference in OS was evident in the subgroup of pts who had relapsed within a year of auto-SCT compared with those who had relapsed >1 year after auto-SCT. As previously reported, the most common (≥15%) brentuximab vedotin-related adverse events of any grade were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of Grade 3 or higher that occurred in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. Conclusions: After a median observation time of approximately 2.5 years from first dose of brentuximab vedotin, 60 of 102 pts (59%) with relapsed or refractory HL were alive at the time of last follow up and the median OS has not yet been reached. The estimated 24-mo survival rate was 65%. The only pretreatment factor evaluated that was associated with a higher 24-mo survival rate was a baseline ECOG score of 0. Prolonged OS was observed in pts with both long and short progression-free intervals after auto-SCT. Pts who achieved a CR with brentuximab vedotin experienced longer OS than pts who did not achieve a CR. Based upon these findings, combination regimens that incorporate brentuximab vedotin are presently being evaluated in clinical trials to determine whether the proportion of pts who achieve durable CRs might be further increased. Disclosures: Chen: Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel Expenses Other. Gopal:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Ansell:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria. Larsen:Seattle Genetics, Inc.: Employment, Equity Ownership. Sievers:Seattle Genetics, Inc.: Honoraria, Research Funding. Younes:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Affimed: Research Funding; Gilead: Research Funding; Johnson & Johnson: Research Funding.

Abstract 2731 Background: Survivin is responsible for preservation of cell viability and regulation of mitosis in tumor cells. Survivin is overexpressed in the majority of aggressive B-cell lymphomas and thus is an attractive target in subjects with relapsed lymphoma. YM155 is a survivin suppressant that in vitro, when combined with rituximab, synergistically enhances the induction of apoptosis in lymphoma cells. In human DLBCL xenograft models, this combination significantly inhibits tumor growth and prolongs survival. Based on these preclinical combination data and single agent clinical data, a Phase 2 study utilizing YM155 rituximab was initiated. Methods: The study employs a two-stage group sequential method, designed to enroll a total of 40 subjects with an interim futility assessment (Stage I). Eligible patients have histologically confirmed relapsed CD20-positive primary or transformed diffuse large B cell lymphoma (DLBCL) or grade 3 follicular lymphoma (FL) and are either not candidates or previously had an autologous stem cell transplant (ASCT). Subjects had received ≥ 1 prior anthracycline containing regimen with a documented response to the last regimen prior to study entry. Induction, ASCT and maintenance therapy were considered as one regimen. The dosing regimen was YM155 5 mg/m2/day as a 168 hour (7-day) continuous infusion in a 14 day cycle and rituximab 375 mg/m22 Days 1 and 8 cycles 1 – 4 and then repeated every 10 cycles. The primary endpoint of the study is objective response rate (ORR) per modified IWG 2007. Imaging studies are performed every 8 weeks (4 cycles) after initiation of therapy. In order to continue enrolling in the study, an overall response rate of 4/16 (25%) must be achieved. Results from the completed Stage I are reported here. Results: Sixteen subjects, the majority of whom were male 13/16 (81%), were enrolled in Stage I. The median age was 62.9 (range: 32 – 78) with a majority of subjects 15/16 (93.8%) with DLBCL. IPI/FLIPI scores were intermediate in 10 subjects (62.5%) and high in 3 subjects (18.8%). The median number of prior therapies was 2 (range: 1 – 5), 16/16 (100%) of patients received rituximab in 1st or subsequent lines of therapy. Seven patients (43.7%) had prior ASCT. The median number of cycles of YM155 administered was 11 (1–37). The overall response rate was 9/16 (56.3%) with 2/16 (12.5%) CR, 7/16 (43.8%) PR and 4/16 (25%) SD. The median time to response was 53 days (range: 52 – 109). Median duration of response and median PFS has not been achieved. Clinical benefit rate was 13/16 (81.3%). The most common adverse events reported, regardless of relationship, were pyrexia 8/16 (50%), cough 7/16 (43.8%), asthenia 5/16 (31%) and fatigue, back pain, vomiting, neutropenia and thrombocytopenia each 4/16 (25%). Five subjects (31.3%) experience Grade 4 adverse events and 2 (12.5%) had Grade 5 adverse events (disease progression and respiratory failure), neither of which was considered related to therapy. The most common Grade 4 event was neutropenia 4/16 (25%), with all other Grade 4 events occurring in only 1 subject (febrile neutropenia, thrombocytopenia, general physical health deterioration, infusion site extravasation, central line infection, infective thrombosis, mediastinitis, dyspnoea, pleural effusion). Conclusion: In subjects with relapsed aggressive NHL receiving combination YM155 and rituximab, the ORR for Stage I was 56.3%, which exceeds the requirement to continue to Stage II. Overall the combination regimen was well tolerated with limited hematologic toxicities. Stage II enrollment is ongoing. Disclosures: Papadopoulos: Astellas: Consultancy, Research Funding. Steinberg:Astellas Pharma: Employment. Papa:Astellas Pharma: Employment. Keating:Astellas Pharma: Employment.

Abstract 3687 Background Patients ≥60 years of age comprise a significant portion of the population with hematologic malignancies. In addition, advanced age is a known negative prognostic indicator in many cancers including CD30+ malignancies such as Hodgkin lymphoma (HL) and systemic anaplastic large-cell lymphoma (sALCL). Novel treatments with significant antitumor activity and increased tolerability are needed in this patient population that is often underrepresented in clinical trials. Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate (ADC) comprised of the microtubule-disrupting agent monomethyl auristatin E (MMAE) conjugated to an antibody that binds human CD30. This ADC has been studied in 2 phase 2 single-arm studies of patients aged ≥12 years with relapsed or refractory CD30+ lymphomas (median age 36.5, 13% ≥60). Brentuximab vedotin (1.8 mg/kg) administered once per 3-week cycle demonstrated objective response rates (ORRs) of 75% and 86% and complete remission (CR) rates of 34% and 57%, in HL and sALCL patients respectively. These objective responses were durable with a median duration of 6.7 and 13.0 months, respectively. The 3 most common adverse events (AEs) in HL and sALCL patients were peripheral sensory neuropathy (42% HL, 41% sALCL), nausea (35% HL, 40% sALCL), and fatigue (34% HL, 38% sALCL). Grade ≥3 neutropenia was observed in 20% of HL patients and 21% of sALCL patients. Methods This study presents a retrospective analysis of a subset of 40 patients aged 60 years or older with relapsed or refractory CD30+ lymphomas who received brentuximab vedotin in 1 or more of 7 clinical studies. Patients enrolled in the hepatic/renal impairment arm of a brentuximab vedotin pharmacokinetics study were excluded. The dosing schedule was either weekly (range 0.6–1.0 mg/kg) or every 3 weeks (range 1.2–2.7 mg/kg) with most patients receiving 1.8 mg/kg IV every 3 weeks. Antitumor activity was assessed by best response according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). AEs were continually monitored in all studies from the start of dosing to 30 days after the last dose. Results The median age of patients was 66 years (range 60–82). There were 22 sALCL patients and 15 HL patients (median age 66.5 and 68.0 years, respectively) in the analysis set. Three patients (8%) were diagnosed with other CD30+ lymphomas and had a median age of 62.0 years. The majority of patients were male (65%). Patients had received a median of 2.0 prior cancer-related systemic therapies (range 1–6) and 34 of 40 had received a prior stem cell transplant. Baseline B symptoms were reported in 8 patients (20%). Patients received a median of 7.5 cycles (range 1–22) of single-agent brentuximab vedotin treatment with a median dose intensity of 0.56 mg/kg/week (range 0.3–0.9). All sALCL patients and 53% of HL patients achieved an objective response (CR rate, 50% and 40%, respectively). Across diagnoses, the ORR was 78% with 43% of patients achieving a CR. The median duration of response was 13.0 months for sALCL patients and was not reached in HL patients at the time of analysis. Resolution of B symptoms was observed in half of the patients (4 of 8) who presented with baseline B symptoms. Treatment-emergent AEs of any grade (incidence ≥30%) included fatigue (58%), peripheral sensory neuropathy (58%), and nausea (38%). Treatment-emergent AEs ≥ Grade 3 in severity (incidence ≥20%) included neutropenia (25%) and anemia (20%). Serious adverse events (SAEs) were reported in 53% of patients with the most common (≥10%) being mental status changes (10%). AEs leading to treatment discontinuation occurred in 30% of patients. Death occurred within 30 days of the last dose in 1 patient with the cause of death considered unrelated to brentuximab vedotin or disease. Overall, 30% of patients received growth-factor support. Conclusions Brentuximab vedotin showed substantial antitumor activity and evidence of B-symptom resolution in these patients ≥60 years of age. Antitumor activity and the durability of clinical responses were consistent with those observed in the phase 2 studies of patients aged ≥12 years. AEs of fatigue and sensory neuropathy were more frequent in the older population, while other AEs such as nausea and neutropenia occurred with a similar incidence as in the phase 2 studies. Future studies will explore the safety and efficacy of brentuximab vedotin in earlier lines of therapy for this underserved population. Disclosures: Fanale: Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Younes:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Affimed: Research Funding; Gilead: Research Funding; Johnson & Johnson: Research Funding. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel Expenses Other. Friedberg:Seattle Genetics, Inc.: Consultancy, Research Funding. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Zain:Seattle Genetics, Inc.: Honoraria, Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Gopal:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding.

Abstract 3131 Patients with relapsed or refractory Hodgkin's Lymphoma (HL) who fail autologous transplantation seldom survive long term and most have exhausted effective therapeutic options. Preliminary data however suggests a role for allogeneic transplantation (allo-SCT) using reduced intensity conditioning (RIC), with 2–5 year progression free survival (PFS) and overall survival (OS) of 20–36% and 28–64%, respectively. Allo-SCT for HL is still uncommon however with CIBMTR data indicating a median of only 2 allografts/center/year (range: 1–13) at US centers. Methods We report 7 year outcome on 31 consecutive patients with HL who failed an autograft who were prospectively enrolled in a single institution trial and treated with BEAM RIC regimen (BCNU 300mg/m2 day -6, Etoposide 100mg/m2 daily and Cytarabine 100mg/m2 BID days -5 to -2, and Melphalan 140mg/m2 day -1). Graft vs host disease (GVHD) prophylaxis was with tacrolimus (0.03mg/kg/day starting day -2) and methotrexate (5mg/m2 days +1,+3,+6). Antithymocyte globulin (ATG 1.5mg/kg/day on days -4, -3) was used in 17 patients who underwent matched unrelated donor (MUD) transplantation and had no cytotoxic chemotherapy in the preceding three months. Results Median time from diagnosis to allo-SCT was 51 months (range: 17–172) and median age was 36 (range: 21–55 years). Patients were heavily pretreated with a median number of 5 prior regimens (including autograft; range: 4–9). Thirteen patients received stem cells from an HLA-matched sibling, 12 MUDs, 5 mismatched unrelated and 1 had mismatched related stem cells. All patients engrafted promptly at a median of 15 days (range: 12–26) defined as an absolute neutrophil count of >0.5 × 109/L and a median of 26 days (range: 10–76) for unsupported platelets >20 × 109/L. 100-day chimerism results were available for 26 patients: 23 (88%) were full donor chimeras (>98% donor DNA), 1 was a mixed chimera at 96% donor DNA, and one patient had graft rejection. The incidence of grade 1–2 acute GVHD was 29% and grade 3–4 was 7%. Incidence of limited stage chronic GVHD (cGVHD) was 56% and extensive stage was 9%. At a median follow up of 7 years the PFS is 36% (95% CI 19–54%) and OS is 42% (95% CI 23–59%), with no relapses seen after 36 months. Non-relapse mortality at one year was 13% (95% CI 5–32%). Significant predictors of improved survival in univariate analysis included chemosensitivity, bulk of disease Conclusion RIC BEAM allogeneic transplantation is safe and effective in producing long term remissions in patients with advanced HL who fail autografts. Bulk of disease is the only significant prognostic factor for a successful outcome regardless of chemosensitivity, thus patients with chemorefractory disease should be offered an allo-SCT after additional therapy has been given to achieve a minimal residual disease state, e.g with brentuximab vedotin and/or involved field radiation. While very preliminary, brentuximab vedotin also appears promising in the treatment of relapsed HL after allograft failure and thus should be further explored as maintenance therapy after engraftment to reduce early relapses while awaiting a potential graft vs Hodgkin's effect. Disclosures: Rodriguez: Seattle Genetics, Inc: Research Funding. Smith:Seattle Genetics, Inc: Consultancy, Research Funding. Stiff:Seattle Genetics, Inc: Research Funding.

Abstract 3102 Identifying the optimal patients and timing for allogeneic hematopoietic stem cell transplant (HSCT) is an ongoing challenge for transplant centers that requires assessment of more than just the disease status and stage. Pre-existing co-morbidities also independently impact both 100 day and 1 year non-relapse mortality (NRM) as well as long term overall survival. Additionally, the CIBMTR has also shown that Hispanic patients have an inferior survival after allogeneic HSCT, although why ethnicity is linked to a higher mortality, e.g. is it higher risk/timing of transplant, lower socioeconomic status, increased co-morbidities, etc. however, is still undetermined. A survival analysis of allogeneic HCT outcomes that includes ethnicity, co-morbidity, insurance payor, as well as traditional risk factors such as age, disease risk at transplant, and remission status would be helpful to clarify the outcome disparities found in different ethnic subgroups and more importantly lead to strategies to minimize the effect. Methods: We performed a retrospective analysis of the outcome of 363 consecutive adult allogeneic transplants at Loyola University Hospital of whom approximately 10% were Hispanics (34) from January 1, 2003 to June 30, 2010. We use a focused approach to optimize care of non-English speaking Hispanics which involves native speakers at all levels, written materials in Spanish, and an IRB approved method to permit all non-English speaking patients to enroll in all clinical trials is present. Traditional prognostic data as well as the Sorror co-morbidity index and socioeconomic and ethnicity status were determined for each patient. The surrogate we used for socioeconomic status was insurance payor (i.e. indigent + Medicaid vs. third party insurance/Medicare). Survival analysis was calculated using Kaplan Meier plots considering each patient at 100 days, 1 year, and 3 years. Results: The median age for the 363 patients was 47.1 years with 48.7% being in the High Risk CIBMTR category, and 74.1% being in remission at transplant. The median co-morbidity index was 2.0. No differences were seen in remission status or the co-morbidity index for Hispanic vs. non-Hispanic patients, while fewer Hispanic patients were in the High CIBMTR Risk group (27.3 vs. 50.9%; p = .048). Survival for Hispanics (34) vs. non-Hispanics (329) showed no difference in overall survival at three years (42.1 vs. 42.8%). Based on payors, we found no statistical difference in 100 day overall mortality after HSCT for those with Medicaid (n = 35) vs. non-Medicaid (n = 328) payors with Hispanic non-Medicaid and non-Hispanic non-Medicaid survivals at 100 days of 82.8 and 87.9%. However despite the relatively small number, both the non-Hispanic and Hispanic patients with Medicaid showed a significantly decreased survival after 100 days with 3 year survivals of 20.0 and 30.0% for Hispanic and non-Hispanic Medicaid patients vs. 51.7 and 56.7% of the Hispanic and non-Hispanic non-Medicaid groups respectively (p = .002). Conclusions: Unlike prior reports, and perhaps by using a focused approach for our non-English speaking Hispanic patients, we found no difference in survival between Hispanics and non-Hispanics in our series of 363 consecutive allografts at 100 days, 1, or 3 years, although they may have been predicted to have had a slightly better prognosis based on a better Risk Group status. We did however find that payor was an important prognostic variable for outcome after the first 100 days regardless of ethnicity. Whether this is simply due to the financial toll of such a chronic illness and therapy remains to be seen, but this suggests that closer follow-up after day 100 may be of significant benefit for this subgroup of patents which may grow due to health care reform. Disclosures: No relevant conflicts of interest to declare.

Background Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells. Results Ezatiostat was administered to 19 patients with non-deletion(5q) myelodysplastic syndrome (MDS) at one of two doses (2000 mg or 2500 mg/day) in combination with 10 mg of lenalidomide on days 1–21 of a 28-day cycle. No unexpected toxicities occurred and the incidence and severity of adverse events (AEs) were consistent with that expected for each drug alone. The most common non-hematologic AEs related to ezatiostat in combination with lenalidomide were mostly grade 1 and 2 fatigue, anorexia, nausea, diarrhea, and vomiting; hematologic AEs due to lenalidomide were thrombocytopenia, neutropenia, and anemia. One of 4 evaluable patients (25%) in the 2500/10 mg dose group experienced an erythroid hematologic improvement (HI-E) response by 2006 MDS International Working Group (IWG) criteria. Four of 10 evaluable patients (40%) in the 2000 mg/10 mg dose group experienced an HI-E response. Three of 7 (43%) red blood cell (RBC) transfusion-dependent patients became RBC transfusion independent, including one patient for whom prior lenalidomide monotherapy was ineffective. Three of 5 (60%) thrombocytopenic patients had an HI-platelet (HI-P) response. Bilineage HI-E and HI-P responses occurred in 3 of 5 (60%), 1 of 3 with HI-E and HI-N (33%), and 1 of 3 with HI-N and HI-P (33%). One of 3 patients (33%) with pancytopenia experienced a complete trilineage response. All multilineage responses were observed in the 2000/10 mg doses recommended for future studies. Conclusions The tolerability and activity profile of ezatiostat co-administered with lenalidomide supports the further development of ezatiostat in combination with lenalidomide in MDS and also encourages studies of this combination in other hematologic malignancies where lenalidomide is active. Trial registration Clinicaltrials.gov: NCT01062152

Consistent loss of DNA sequences from several regions on the short arm of human chromosome 3 has suggested that multiple tumor suppressor genes reside on chromosome 3p in various types of cancer cells. We have focused our efforts on an analysis of chromosomal band 3p21.1 since aminoacylase-1 (ACY1), which is localized to this band, has been shown to have lower levels of expression in several small cell and non-small cell lung cancer cell lines. Starting with two cosmids within 3p21.1, D3S92 and D3S93, we have isolated two separate contigs of overlapping cosmids within 3p21.1, by screening a library of 5700 chromosome 3-specific cosmid clones. Detailed restriction maps for these two contigs show that they contain multiple clusters of rare cutting restriction endonuclease sites. One contig extends for 100 kb and encompassed both ACY1 and D3S92, and the other extends about 80 kb around the D3S93 locus. Many different restriction fragments derived from these two contigs were found to be evolutionarily conserved and hybridized to distinct message transcripts. These fragments were used to identify homologous cDNAs from an adenogastric cDNA library, and several of these cDNAs were partially sequenced. We have identified five new genes from these two contigs and there is evidence to suggest that several additional genes reside within these cosmid contigs. The genes identified from 3p21.1 were then hybridized to DNA, isolated from a series of lung cancer cell lines and matched normal and tumor DNA from lung cancer patients. No alterations were detected with any of these probes, both at the DNA or RNA levels. A similar analysis with DNA fragments derived from these two genomic regions also failed to detect any alterations.

Deletion of DNA sequences from at least three different regions on the short arm of human chromosome 3 (3p13–14, 3p21 and 3p25) are frequently observed during the development of many solid tumors, including lung cancers and renal cell carcinomas. In order to physically characterize the 3p21 region, we previously identified a radiation fusion hybrid that contained about 20 megabases of DNA from chromosome region 3p14.2–p21.3. In this study total Alu-PCR products from this hybrid were used as a probe to isolate 86 yeast artificial chromosomes (YAC) clones from a 620-kb average insert YAC library (ICRF). Sixty-nine Alu-PCR markers, generated from the YACs, and seven PCR primers were used to screen for overlaps between individual clones. Seven contigs were identified encompassing 32 YAC clones. Based on previous information about localization of the PCR primers, the three largest contigs could be assigned to smaller subregions between 3p14.2 and 3p21.3. By this work a large proportion of the 3p14.2–21.3 region is covered with large-insert YAC clones.

Abstract 3668 Background: The prevalence of NHL in patients (pts) ≥ 80 years has recently tripled; however, data on prognostic factors and treatment for this very elderly population is sparse. Methods: A multicenter retrospective analysis of NHL pts ≥80 years diagnosed between (1999–2009) was completed. Detailed characteristics obtained include geriatric syndromes (GS), activities of daily living (ADLs), and co-morbidities using the Cumulative Illness Rating Scale-Geriatrics (CIRS-G). Further, univariate associations with survival were determined, while a multivariate Cox regression proportional hazards model was performed. Results: We identified 303 pts: 170 aggressive NHL (84% B-cell and 16% T-cell) and 133 indolent NHL (82% B-cell and 18% T-cell). Median age was 84 years (range 80–95). Poor performance status (PS), high LDH, and extranodal disease were more common in aggressive vs. indolent NHLs (P=0.004, 0.005, and 0.002, respectively). Furthermore, aggressive NHL pts presented more frequently with advanced stage and higher relative prognostic scores (P=0.0002 and 0.003 respectively). Loss of any ADL was more frequent in aggressive histology (P=0.002). Diffuse large B-cell NHL was the most common histology overall, while follicular lymphoma was the most diagnosed indolent NHL. At least one GS was present in 80 pts (26%) with dementia being most common (26%). Loss of at least one ADL was seen in 14%, while 30% of pts were considered “non-fit” at diagnosis. Of available treatment data in aggressive B-NHL, 62% received rituximab (R)-containing regimen and 18% received chemotherapy without R. Those with aggressive T-cell NHL were treated with systemic therapy in 74%, topical in 15%, radiation in 4%, and no therapy in 7%. Indolent B-cell NHL had observation in 38% for a median of 26 months, R alone in 21%, R plus chemotherapy in 15%, radiation alone in 7%, and chemotherapy alone in 9%. Cutaneous T-cell pts received topical therapies in 42%, systemic therapy in 29%, and radiation alone in 17%. At 49-month median follow-up, 4-year progression-free (PFS) and overall survival (OS) for aggressive NHL were 31% and 44%, respectively (stage I/II: PFS 53% and OS 66%; stage III/IV: PFS 20% and OS 32%; p Conclusion: To our knowledge, this represents the largest analysis of very elderly NHL reported to date. We identified that loss of ADL's and lack of CR to initial treatment were robust predictors of survival in very elderly NHL, irrespective of histology, and they superseded the prognostic value of either PS or age. Geriatric assessments, including ADLs, are powerful predictors of outcome in very elderly NHL and should be prospectively studied. Disclosures: No relevant conflicts of interest to declare.

Abstract 4625 Background: Gene silencing via methylation of CpG islands in the promoter regions of many genes but specifically of APAF1, p15INK4B, p16INK4A, RARB, and CDH1 appears to play a role in pathogenesis of myeloid malignancies. Azacitidine (AZ) causes demethylation by inhibiting DNA methyltransferase and has already been shown to be an effective therapy for myelodysplastic syndromes. The demethylation induced by AZ is detectable in about 48 hours and increases significantly after 5 days of therapy. After that, the effect tends to plateau. Methods: We initiated a Phase 2 study of patients with non-BCR-ABL MPDs to determine clinical response to AZ therapy and correlate it with promoter DNA methylation and gene re-expression. The protocol was approved by the institutional IRB. Patients received AZ 75mg/m2 s/c for days 1–7 and repeated every 28 days for a minimum of 4 cycles. Responders were allowed to continue treatment until disease progression. Pretreatment and D 7 peripheral blood samples were analyzed for promoter methylation status and expression of the 5 genes mentioned above. Bisulfite conversion of DNA was followed by quantitative PCR using primers specific for methylated or for unmethylated promoter regions. For gene re-expression analysis, quantitative RT-PCR was performed with RNA isolated from the same patient samples and the same time points as the DNA methylation analyses. Results: Seven patients were enrolled before the study closed due to lack of accrual. The diagnoses were: Myelofibrosis (MF) 4, essential thrombocythemia 1, unclassified MPD with dysplasia 2. One patient with MF and one with unclassified MPD responded, the latter with normalization of marrow karyotype. Both responses were accompanied by significant decrease in APAF1 promoter methylation and surprisingly, an increase in promoter methylation of RARB. In three of the non-responders, APAF1 methylation increased. In patients with decreased Apaf1 methylation, a statistically significant increase in mRNA expression was observed. Conclusions: Within its limitations, this small trial shows that the methylation status of selected genes, particularly of APAF1 and RARB (inversely) is associated with response to treatment with azacitidine in patients with MPDs. In non-responders, Apaf1 methylation appears to increase. A larger study will be necessary to confirm these preliminary observations. Disclosures: Smith: Seattle Genetics, Inc.: Research Funding; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Spectrum: Consultancy; GSK: Speakers Bureau. Nand:Celgene Corporation: Research Funding.

Abstract 2625 Purpose. Survival rates for eHL (most commonly defined as age over 60 years) are significantly and disproportionately inferior to those achieved in younger patients (pts). Reported 5-year event-free survival (EFS) rates for advanced-stage eHL have historically ranged from 30%–45% with 5-year overall survival (OS) rates of 40%–55%. Potential explanations for these discrepant inferior outcomes include co-morbidities precluding delivery of chemotherapy, treatment-related toxicities, and biology of disease. Data examining toxicity, survival, and prognostication for eHL in the modern era are lacking. Methods. We report a multicenter collaboration that retrospectively investigated a large cohort of eHL pts treated over a recent 12-year period (June 1999 December 2010). We examined clinical characteristics, treatment-related toxicities, and outcomes. Furthermore, comorbidities were assessed using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) scale. Patients were also classified as “fit” vs “not fit” (i.e., loss of activities of daily living (ADLs), >3 grade 3 CIRS-G, any grade 4, and/or presence of geriatric syndrome). Univariate associations with survival were determined, while a multivariate Cox proportional hazards model was completed. Additionally, a prognostic model was constructed by classification and regression tree (CART) analysis. Results. 113 eligible pts were identified, while 95 had full data and were analyzed. Among these 95 pts (58M:37F), median age was 67 years (range, 60–89), with 33% of pts ages 70–79 years, while 7% were 80–89 years. 27% of pts had a prior malignancy at a median of 8.4 years (range, 1–25 years) prior to HL diagnosis, for which most had received radiation. At HL diagnosis, there were presence of B symptoms in 54%, performance status 2–4 in 27%, 21% with history of coronary artery disease, and 16% had diabetes. In terms of functional status, 61% of pts had a CIRS-G grade 3 or 4 in at least 1 category, while 46% had a cumulative score >6. Further, 17% had presence of a geriatric syndrome, 26% were classified as 'not fit', and 13% had loss of ADLs at time of HL diagnosis. 25% of pts had bone marrow involvement, while 20% had other extranodal disease (most common: bone and lung). Altogether, 64% of pts had stage III/IV disease, of which 58% had an international prognostic score (IPS) of 4–7. HL histology was nodular sclerosis in 47%, mixed cellularity 31%, NOS 16%, lymphocyte predominant 5%, and lymphocyte depleted 1%. Primary treatment consisted of: ABVD-based (n=67), MOPP-based (n=6), BCVPP (n=6), ChlVPP (n=5), radiation alone (n=4), CHOP (n=3), hospice (n=2), BEACOPP (n=1), and watchful waiting (n=1). 78% of pts received granulocyte-colony stimulating factor (G-CSF) with therapy. The overall response rate (ORR) among treated pts was 85% (73% complete remission (CR) rate). In terms of toxicity, the incidence of bleomycin lung toxicity (BLT) was 32%, which had an associated mortality rate of 25%. Notably, the incidence of BLT was 37% vs 0% among pts who received G-CSF vs not, respectively (p=0.041). With a median follow-up of 66 months (6–154) months, the 5-year EFS and OS for all eHL pts were 44% and 58%, respectively (stage I/II: 61% and 79%; and stage III/IV: 36% and 46%; p=0.009 and p=0.001, respectively). Prognostic factors that predicted survival on univariate analysis are detailed in Table 1. On multivariate regression analysis, 2 factors were associated with inferior survival: 1) age ≥ 70 years (EFS: 1.76 (95%CI 0.98–3.16), p=0.06; and OS: 2.24 (95%CI 1.16–4.33), p=0.02) and 2) Loss of ADLs (EFS: 2.47 (95%CI 0.98–6.21), p=0.055; and OS: 2.71 (95%CI 1.07–6.84), p=0.04). Furthermore, a survival model by multivariate CART analysis, based on number of these 2 adverse factors (0, 1, 2), was formed: 5-year EFS 73%, 51%, 0%, respectively (p Conclusions. This large, retrospective multicenter analysis of eHL found a high ORR and CR rate, but poor long-term outcomes. As shown previously, a significant percentage of eHL pts suffered BLT, which was fatal in 25% and appeared strongly related to use of growth factors. Further, several geriatric specific variables, including loss of ADL's, was highly predictive of outcome and should be prospectively incorporated into clinical trials. Finally, we developed a new prognostic model for eHL that identifies pt populations with markedly divergent outcomes. Disclosures: No relevant conflicts of interest to declare.

Abstract 2778 Introduction: Lenalidomide is approved for the treatment of del(5q) MDS in US and Japan. In Low to Intermediate-1 (Int-1) risk non-del(5q) MDS, lenalidomide treatment is less effective with a lower response rate (25%) and shorter response duration [Raza A. et al, Blood, 2008.111,1]. Ezatiostat, a glutathione S-transferase P1-1 (GST P1-1) inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in malignant cells. Based on the novel mechanism of action, response rates, non-overlapping toxicities, and tolerability observed in a single agent ezatiostat Phase 2 study in MDS, a study of the combination of ezatiostat and lenalidomide was conducted to determine the safety and efficacy of ezatiostat with lenalidomide in non-del(5q) Low to Int-1 risk MDS. Methods: In this multicenter Phase 1 dose-ranging study, ezatiostat was given at a starting dose of 2000 mg in combination with lenalidomide at 10 mg, days 1–21 of a 28-day cycle. In stage 1, 3–6 patients in a standard 3+3 design were treated before escalation to the ezatiostat/lenalidomide 2500/10 mg dose level. Treatment was given until lack of MDS response or unacceptable toxicity. Hematologic improvement-erythroid (HI-E) rates were determined by the MDS International Working Group (IWG; 2006) criteria. Results: Eighteen pts (median age 73 yrs; range 57–82; 72% male), with World Health Organization classifications: 4 refractory anemia (RA), 2 RA with excess blasts-1, 4 refractory cytopenia with multilineage dysplasia (RCMD), 5 RCMD with ring sideroblasts, 2 MDS-unclassified, 1 MDS/myeloproliferative disorder-U were enrolled. Thirteen pts (72%) were Int-1 risk, 5 (28%) Low risk; 4 pts (22%) had abnormal cytogenetics. Twelve RBC transfusion-dependent pts (67%) required a median of 6 units (range 4–10)/8-weeks. Two pts (11%) were platelet transfusion dependent. A total of 67 treatment cycles were given (median 3.5 cycles/pt [range 1–11]) and only 6 cycles (9%) required dose reductions and 8 (12%) dose delays. Two of 6 pts reported DLTs (Grade 3 diarrhea and Grade 3 rash) at 2500/10 mg, with 9 additional pts receiving the recommended combination dose of 2000/10 mg. Eleven of 18 pts were evaluable (4 at 2500/10 mg and 7 at 2000/10 mg), and 3 pts are still on therapy with insufficient treatment duration to be evaluable. The HI-E rate was 43% (3/7; 95% CI, 10%–82%) for pts at the recommended 2000/10 mg dose and 6 pts are continuing therapy at the time of analysis. Three of 8 (38%; 95% CI, 9%–76%) RBC transfusion-dependent evaluable pts achieved transfusion independence including 1 responder who did not respond to prior lenalidomide. In responders, the median increase in hemoglobin level was 3.4 g/dL (from 7.9 g/dL). In 2 of 4 thrombocytopenic pts, a HI-platelet (HI-P) response was observed. A bilineage (HI-E and HI-P) response in 2 of 4 pts with anemia and thrombocytopenia was reported. One RBC and platelet transfusion-dependent pt who had a poor response to prior anti-thymocyte globulin treatment achieved complete RBC and platelet transfusion independence. The combination was generally well tolerated with no unexpected toxicities. Most common treatment-related non-hematologic adverse events (AEs) were Grades 1 and 2 including: fatigue (6%, 28%), swelling (0%, 11%), anorexia (11%, 6%), rash (0%, 6%), skin odor (11%, 6%), nausea (39%, 11%), diarrhea (22%,17%), vomiting (28%,17%), upper abdominal pain (5.6%, 5.6%), and constipation (11%, 0%). Grade 3 events were rash (11%), nausea (6%), diarrhea (17%), and vomiting (6%). Most common hematologic-related AEs were Grades 1 and 2 thrombocytopenia (11%, 6%) and neutropenia (0%, 11%). Grade 3–4 AEs were thrombocytopenia (11%, 17%), neutropenia (17%, 11%), anemia (6%, 6%), and febrile neutropenia (11%, 0%). Conclusions: Ezatiostat is the first GST P1-1 inhibitor to cause clinically significant reductions in RBC and platelet transfusions, including RBC and platelet transfusion independence. Since ezatiostat is non-myelosuppressive, it is a good candidate for combination with lenalidomide and in this study, the combination was well tolerated. Interestingly, ezatiostat may also have the potential to enhance lenalidomide's efficacy. The recommended doses of this combination regimen for future studies is the ezatiostat/lenalidomide 2000/10 mg. Disclosures: Off Label Use: Lenalidomide was used off-label in patients with non-del5q MDS. Mulford:Celgene: Speakers Bureau. Brown:Telik, Inc.: Employment, Equity Ownership. Meng:Telik, Inc.: Employment, Equity Ownership. Lyons:Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Mesa:NS Pharma: Research Funding; Astra Zeneca: Research Funding; SBio: Research Funding; Lilly: Research Funding; Incyte: Research Funding; Celgene: Research Funding.

Abstract 3711 Background: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). Trials with brentuximab vedotin have previously reported results in patients with relapsed or refractory HL or sALCL. In a pivotal HL trial, complete remissions (CRs) were observed in 35 of 102 patients (34%) with a median duration of 20.5 months (Chen 2011). Thirty-three of 58 patients (57%) with sALCL achieved CRs with a median duration of 13.2 months in a phase 2 trial (Pro 2011). In both of these studies, a maximum of 16 cycles was permitted; patients with HL received a median of 10 cycles and those with sALCL, 7 cycles. This case series presents a retrospective analysis on a subset of patients who have received prolonged treatment (>16 cycles) with brentuximab vedotin in a treatment-extension study (ClinicalTrials.gov #NCT00947856). Methods: Brentuximab vedotin 1.2 or 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment in 1 of 4 preceding studies. Consecutive cycles of treatment were then administered in the extension study until disease progression, unacceptable toxicity, or withdrawal of consent. Antitumor activity in this case series was based on objective response assessments per the investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: Fifteen patients have received >16 consecutive cycles of treatment with brentuximab vedotin. The median age of patients was 35 years (range 14–74); 9 patients were female. Patients had relapsed or refractory CD30-positive HL (10) or sALCL (5) and had received a median of 3 prior therapies (range 1–14). Nine patients had previously failed autologous stem cell transplant (SCT), and 2 of these patients had additionally failed an allogeneic SCT. The median number of treatment cycles was 19 (range 17–29). At the time of the analysis, 2 patients had discontinued treatment; neither patient had discontinued due to an adverse event (AE). AEs among patients were generally mild, which enabled continued treatment beyond the initial study. Across all cycles of treatment, AEs in >30% of patients were peripheral sensory neuropathy (73%), fatigue (53%), upper respiratory tract infection (53%), cough (40%), alopecia, diarrhea, neutropenia, and pyrexia (33% each). The only AE which occurred for the first time after Cycle 16 in more than 1 patient was neutropenia (n=2). Peripheral neuropathy events (by Standardised MedDRA Query) of Grade 1 or 2 were experienced by 87% of patients; no Grade 3 or 4 events of peripheral neuropathy were observed. Peripheral neuropathy was managed with dose reductions and dose delays; resolution or improvement of peripheral neuropathy was observed in over half of the patients (7 of 13) with a median time to resolution or improvement of 3.1 weeks (range 0.1–8). Best clinical responses in patients were 11 CRs, including CRs achieved by all 5 patients with sALCL, 2 partial remissions (PRs), and 2 patients with stable disease. Four of 11 patients evolved from a PR to achieve a CR; the median time from first dose to achievement of CR was 12 weeks (range 5.4–48.9). The median duration of objective response has not been reached; the durations ranged from 6.5+ to 21.8+ months. At the time of the analysis, 14 patients were alive and free of documented progression, and the median progression-free survival had not been reached (range 11.8+ to 23+ months). Conclusions: Among patients with relapsed or refractory HL or sALCL who have enrolled in a treatment-extension study, 15 have received >16 consecutive cycles of treatment with brentuximab vedotin. The safety profile of brentuximab vedotin did not meaningfully change with treatment beyond 16 cycles. Durations of response (11 CR and 2 PR) ranged from 6.5+ to 21.8+ months, with 13 patients still receiving treatment. Updated safety and durability of response will be presented at the meeting. Disclosures: Forero-Torres: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Berryman:Seattle Genetics, Inc.: Research Funding; Soligenix: Research Funding; Gloucester Pharmaceuticals: Research Funding. Advani:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gopal:Seattle Genetics: Consultancy, Honoraria, Research Funding; Millennium: Honoraria, Speakers Bureau; Cephalon: Research Funding; Spectrum: Research Funding; Piramal: Research Funding; Merck: Research Funding; Calistoga: Research Funding; Abbott: Research Funding; Pfizer: Research Funding; SBIO: Research Funding; Gilead: Research Funding; Genzyme: Speakers Bureau; Amgen: Speakers Bureau; Cellular Therapeutics Inc.: Speakers Bureau. O'Connor:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Purdue Pharma: Consultancy; Celgene: Consultancy; Merck: Research Funding. Olshefski:Seattle Genetics, Inc.: Research Funding. Smith:Seattle Genetics, Inc.: Research Funding; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Spectrum: Consultancy; GSK: Speakers Bureau. Grove:Seattle Genetics, Inc.: Equity Ownership; Seattle Genetics, Inc.: Employment. Matous:Seattle Genetics, Inc.: Research Funding; Celgene: Speakers Bureau; Cephalon: Speakers Bureau; Millennium: Speakers Bureau.

8042 Background: Ages > 80 represent the most rapidly growing segment of society. Incidence of NHL rises exponentially with age; however, sparse data exist among the > 80 pt group. Methods: We comp...

8031 Background: CD30 expression by Reed-Sternberg cells is a defining feature of HL. Brentuximab vedotin comprises an anti-CD30 antibody conjugated by a plasma-stable linker to the potent antimicr...

The t(3;6)(p14;p11) chromosome translocation was identified in a family in which three members developed hematologic malignancies. To help characterize the region on chromosome 3 surrounding this translocation breakpoint, two flanking lambda clones, MS156 and MJ1525, were linked by pulsed-field gel electrophoresis to the same 510-kb NotI fragment on chromosome 3. MS156 was localized to a region proximal to the breakpoint of a der(3) chromosome somatic cell hybrid (derived from the t(3;6) cell line), and MJ1525 localized distal to the breakpoint. MJ1525 was used to screen the CEPH yeast artificial chromosome (YAC) library, which revealed a YAC, 195F3, that spanned the breakpoint. Subcloning into Lambda DASH II and production of a contiguous array of overlapping lambda clones revealed a clone, L17, that spanned the breakpoint. A rare restriction endonuclease map for the YAC 195F3 was constructed, and multiple clusters of rare restriction sites within the YAC were identified, possibly indicating the disruption of a gene by the t(3;6) translocation breakpoint.

Abstract 2142 Background: VCR is an important component of the treatment of ALL, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma, and other adult and childhood cancers. In part, because of the cell cycle specific activity of VCR, its anti-cancer activity is believed to be very exposure time and concentration dependent. Standard dosing of conventional VCR (1.4 mg/m2 with a 2 mg cap) is limited because of early onset peripheral neuropathy and fails to achieve sustained VCR delivery. VSLI (Marqibo) is a nano-particle encapsulated formulation of VCR designed to facilitate dose intensification, prolonged drug delivery and enhanced cancer penetration and concentration. Methods: In a pivotal, Phase 2, multi-national study (RALLY Trial), 65 adults with Philadelphia chromosome negative ALL who were either in second or greater relapse or who had progressed after two or more prior lines of treatment received single-agent intravenous VSLI 2.25 mg/m2 (without any dose cap) weekly over 1 hour as salvage therapy. First-dose PK was investigated in a representative subset of 13 study subjects. Blood for analysis was collected at 8 time points ranging from 5 minutes to 48 hours following infusion. Total VCR plasma levels were determined by HPLC-MS/MS. PK parameters were calculated with Phoenix WinNonlin. Results: The PK subject subset had a median body surface area (BSA) of 1.92 m2 (range 1.47 to 2.45 m2) and received a median VSLI dose (VCR component) of 4.32 mg (range 3.3 to 5.51 mg). Based on BSA and the 2 mg dose cap, all subjects in this study group would have been dosed with 2.0 mg of conventional VCR. The median cumulative induction dose of VSLI (VCR component) that was administered in this study was 18.8 mg (range 3.5 to 70.1 mg). Total VCR plasma concentration decreased rapidly from Cmax after the VSLI infusion in 5 subjects (38%); 8 subjects (62%) exhibited a delay of 4 to 10 hours before the total VCR plasma concentration began to decrease. The calculated Tmax was 1.3 ± 0.4 hours (range 1.1 to 2.0 hours). The Cmax was 1214 ± 233 ng/mL (range 919 to 1720 ng/mL). The apparent mean half-life was 7.1 ± 3.2 hours. The mean AUCinf was 13,993 ± 6,588 ng hr/mL with a range from 7,167 to 27,233 ng hr/mL. The mean clearance (CL) was 6.4 ± 2.6 mL/min. The mean volume of distribution (Vd) was 0.051 ± 0.018 L/Kg. There were no significant differences in the PK parameters between the male and female subjects participating in this study. The table below presents VSLI PK parameters in addition to historical PK parameters for conventional VCR dosed at 2 mg. Conclusions: VSLI clearly provides dose intensification and prolonged VCR delivery compared to conventional, non-encapsulated VCR. VSLI, as dosed in this adult ALL clinical trial, delivered individual and cumulative amounts of VCR that exceed those achievable with standard and approved dosing of conventional VCR. This translated into a median dose intensification of 116% (range 65 to 176 percent) calculated as the percent change in VSLI dose from a standard VCR dose. This dose intensification is believed to have contributed to the 35% overall response rate including 20% complete responses (with or without full blood count recovery) reported in this heavily pre-treated, multiply-relapsed/refractory population without apparent enhanced toxicity [J Clin Oncol 28:15s, 2010 (suppl; abst 6507)]. VSLI has a distinctly different PK profile than conventional VCR. The larger VSLI Cmax and AUCinf reflect the dose intensification afforded by a larger mg/m2 dose and lack of dose capping. Even in the absence of dose capping, the 2.25 mg/m2 VSLI dose represents a 61% dose escalation above conventional VCR. While Cmax and AUCinf are dose-dependent PK parameters, the observed differences between VSLI and VCR control cannot be explained by dose alone. The larger AUCinf also reflects prolonged circulation afforded by the sphingomyelin:cholesterol liposome encapsulation. The modest VSLI mean CL and small Vd reflect the retention of encapsulated VCR within the plasma compartment for an extended period of time so that VCR can better penetrate and accumulate in sites of cancer through fenestrated vasculature. The enhanced delivery of encapsulated VCR contributes to maintenance of VCR concentrations above the effective concentration. Disclosures: Silverman: Hana Biosciences: Employment. Deitcher: Hana Biosciences: Employment.

Abstract 283 Background: Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The antibody-drug conjugate (ADC) brentuximab vedotin (SGN-35) delivers the highly potent antimicrotubule agent monomethyl auristatin E (MMAE) to CD30-positive malignant cells by binding specifically to CD30 on the cell surface and releasing MMAE inside the cell via lysosomal degradation. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest, and results in apoptotic death of the CD30-expressing tumor cell. In a previous phase 1 study with brentuximab vedotin dosing every third week, 11 of 12 patients (92%) treated at the maximum tolerated dose of 1.8 mg/kg had tumor reductions and 6 of 12 patients (50%) achieved an objective response (complete remission [CR] + partial remission [PR]). Methods: A pivotal, phase 2, single-arm, multicenter study was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory HL post autologous stem cell transplant (ASCT). Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. The primary endpoint was the overall objective response rate (ORR) as assessed by an independent review facility according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: A total of 102 patients with relapsed or refractory HL were treated at 26 study centers. Median age was 31 years (range 15–77) and approximately half of the patients were female (53%). Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 (41%) or 1 (59%). All patients had previously received an ASCT and the median number of prior chemotherapy regimens was 4 (range 1–13). More than 70% of the patients had primary refractory disease, defined as failure to achieve a CR or progression within 3 months of completing frontline therapy. In addition, 39% of patients had lymphoma that was refractory to the most recent salvage therapy excluding ASCT. The median duration of brentuximab vedotin treatment on this study was 27 weeks (range 3–54) and the median number of cycles was 9 (range 1–16). The most common (>15%) treatment-related adverse events (AEs) of any grade were peripheral sensory neuropathy (43%), fatigue (40%), nausea (35%), neutropenia (19%), diarrhea (18%), and pyrexia (16%); most events were Grade 1 or 2. Grade 3 treatment-related AEs reported in >1 patient were neutropenia (14%), peripheral sensory neuropathy (5%), thrombocytopenia and hyperglycemia (3% each), and fatigue (2%). The only Grade 4 treatment-related events were neutropenia (4%), and thrombocytopenia, abdominal pain, and pulmonary embolism (1% each). No related Grade 5 events were observed. 18 patients discontinued treatment due to an AE. Consistent with findings from the phase 1 study, 97 patients (95%) had a reduction in tumor size per investigator assessment. Of the 35 patients who had B symptoms at baseline, 29 (83%) experienced resolution of these symptoms. The median time to B symptom resolution was 3 weeks (range Conclusions: Brentuximab vedotin was associated with manageable adverse events and, based on investigator assessment, demonstrated encouraging activity in heavily pretreated patients with relapsed or refractory HL. Tumor shrinkage was observed in 95% of patients and the B symptom resolution rate was 83%. Final results of the independent assessment of ORR, as well as duration of response, progression-free survival, and updated safety data, will be presented at the meeting. Disclosures: Chen: Seattle Genetics, Inc.: Research Funding. Off Label Use: This clinical trial uses the investigational drug, brentuximab vedotin (SGN-35). Gopal:Seattle Genetics, Inc.: Research Funding. Smith:Seattle Genetics, Inc.: Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Klasa:Seattle Genetics, Inc.: Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Engert:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Larsen:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Seattle Genetics, Inc.: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; SBIO: Honoraria, Research Funding.

Abstract 2910 Introduction: MDS is characterized by defects in hematopoietic cell growth, differentiation and apoptosis. Ezatiostat, a glutathione S-transferase inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in leukemic blasts. The purpose of this Phase 2 study was to determine the efficacy and safety of ezatiostat on extended dose schedules in MDS. Methods: Patients (pts) with International Prognostic Scoring System Low or Int-1 risk MDS were enrolled. After initial dose-ranging in 14 pts, subsequent pts were randomized to 2 selected dose schedules: 37 pts at 3 gm daily for 2 weeks followed by a 1-week rest period and 36 pts at 2 gm daily for 3 weeks followed by a 1-week rest period. Treatment was given until lack of MDS response or unacceptable toxicity. A logistic regression analysis was conducted to identify significant MDS disease factors associated with hematologic improvement-erythroid (HI-E) rates as determined by the MDS International Working Group (2006) criteria. Results: Seventy-three pts were median age 73 years (range 48–89) 70% male, and with World Health Organization classification as follows: 11 refractory anemia (RA), 15 RA with ring sideroblasts, 5 RA with excess blasts-1, 24 refractory cytopenia with multilineage dysplasia, 9 MDS-unclassified, 3 MDS/Myeloproliferative disorder-U, 4 MDS-del 5q, and 2 Unknown. Fifty pts (68%) were INT-1 risk, 23 (32%) were Low risk; 27 pts (37%) had abnormal karyotypes with 23 (85%) complex/poor prognostic types. RBC transfusion-dependent pts required a median of 6 (range 4–19) U/8 weeks prior to study entry. Prior treatments included: 34 (47%) DNA methyltransferase (DMTI), 28 (38%) lenalidomide, 56 (77%) erythropoietin, and 32 (44%) growth factors. The HI-E response rate was similar for evaluable pts on the 2 schedules, therefore the data were pooled. The overall HI-E rate was 22% (13/60) [95% CI, 12.1%–34.2%]. The median duration of response was 34 weeks. Eleven of 38 (29%) RBC transfusion-dependent pts had transfusion reductions (reduction of 4U/8weeks) with 4 pts (11%) achieving transfusion independence. A 40% HI-E rate (6/15 pts) [95% CI, 16.3%–67.7%], was observed in pts who had prior lenalidomide, but no prior DMTI, with 5/11 pts (45%) achieving significant RBC transfusion reduction and 3/11 pts (27%) achieving transfusion independence. A 28% HI-E rate (5/18 pts) [95% CI, 9.7%–53.5%] was observed in pts who were lenalidomide and DMTI naive, with 4/8 pts (50%) achieving clinically significant RBC transfusion reduction. Sixteen pts had received prior DMTI but no prior lenalidomide treatment, a 0% HI-E rate (95%CI: 0%-20.6%) was reported. Prior DMTI treatment predicts a 6-fold decrease in the odds for HI-E response to ezatiostat (p=0.027). A 19% HI-Neutrophil (HI-N) rate was observed in 4/21 pts with neutropenia (95% CI, 5.4%–41.9%) and a bilineage (HI-E and HI-N) rate of 20% (95% CI, 5.7%–43.7%) in 4/20 pts with anemia and neutropenia. A 3.7% (95% CI, 0.1%–19%) HI-P rate was observed in 1/27 thrombocytopenic pts and a trilineage (HI-E, HI-N, HI-P) rate of 9.1% (95% CI, 0.2%–41.3%) in 1/11 pts with trilineage cytopenia. There were 2 cytogenetic complete responses, 1 with 45X,-Y[4], 46, XY [16] and 1 with del5q. A total of 431 ezatiostat cycles were given, median 4.0 (range 1–14). Only 15 cycles (3.5%) required dose reduction and 37 cycles (8.6%) dose delays. Most common ezatiostat-related adverse events (AEs) were non-hematologic Grade 1 and 2 gastrointestinal (GI) including: nausea (45%, 17%), diarrhea (25%, 8%), and vomiting (30%, 12%). Grade 3 events were: nausea (1%), diarrhea (3%), and vomiting (2%). Prior DMTI treatment was associated with an increased incidence of GI AEs. Pts with prior DMTI use had GI AEs (Grades 1, 2, 3): nausea (51%, 20%, 2%), vomiting (34%, 7%, 2%), diarrhea (22%, 10%, 5%). DMTI-naive pts had fewer GI AEs (Grades 1, 2, 3): nausea (39%, 15%, 0%), vomiting (26%, 15%, 2%), diarrhea (28%, 7%, 2%). Conclusions: Ezatiostat is the first GSTP1-1 inhibitor shown to cause clinically significant reduction in RBC transfusions, including transfusion independence, as well as HI-N and HI-P. Ezatiostat has shown clinically significant efficacy in lenalidomide naive and lenaliomide treated pts. The tolerability and activity profile of ezatiostat may offer an important treatment option for pts with low to INT-1 risk MDS. Disclosures: Raza: Telik, Inc.: Research Funding. Galili:Telik, Inc.: Research Funding. Godwin:Scripps Health: Honoraria. Boccia:Telik, Inc.: Research Funding. Rarick:Telik, Inc.: Research Funding. Meng:Telik, Inc.: Employment, Equity Ownership. Jones:Telik, Inc.: Employment, Equity Ownership. Brown:Telik, Inc.: Employment, Equity Ownership, Patents & Royalties. Young:Telik, Inc.: Employment, Equity Ownership. Sekeres:Celgene Corp: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Abstract 1355 Background: Overall survival for patients with MM has improved significantly over the past 10 years primarily as a result of novel therapeutics. High dose therapy with ASCT continues to be an effective modality but the progression-free survival following ASCT has improved minimally over the same period of time due to a continued reliance on single agent melphalan. Many chemotherapy/chemoradiotherapy regimens have been used in preparation for stem cell transplantation. However, no regimen has proven superior to high dose melphalan 200 mg/ m2 (MEL 200) which is considered the standard conditioning for patients with MM with relatively predictable results. In order to improve progression free survival (PFS) and overall survival (OS), continued efforts in developing effective preparative regimens are needed. Busulfan is an alkylating agent that affects cells in an AUC-dependent manner. Recent data suggests that the combination of BU and MEL delivers better PFS compared to MEL 200 alone (Grande and Lahuerta; PETHEMA, 36th EBMT meeting. Vienna 2010). Moreover, the addition of bortezomib following MEL 200 appears to increase the VGPR rate when compared to historical cohort receiving MEL 200 alone (Lonial, et al; Blood. ASH Annual Meeting Abstracts, Nov 2008; 112: 3332). Furthermore, the recently published IFM trial of MEL 200 plus BTZ also demonstrated superior response rates and PFS compared to historical controls (Roussel et al Blood. 2010;115:32-7). Rationale: The combination of intravenous BU and MEL followed by BTZ (BuMelVel) will be an effective preparative regimen with acceptable toxicity for patients with MM. Methods: Patients received intravenous BU 130 mg/kg over 3 hours daily × 4 days from D-6 to D-3. Based on the pharmacokinetics of the first two doses, the subsequent 2 doses were adjusted to achieve an AUC of 20,000 mMol-min (5,000 mMol-min/day). MEL was administered at 140 mg/ m2 IV over 15–30 minutes on day -2. Bortezomib was administered IV push over 3–5 seconds on day -1. Bortezomib administration followed a phase I dose escalation design starting at 1.0 mg/m2 for the first cohort; then, 1.3 mg/m2 for the second cohort; then, 1.6 mg/m2/kg for the 3rd cohort and subsequent subjects at the 3rd dose level if no limiting toxicity was observed. Autologous stem cell infusion occurred on day 0. Results: 20 patients have been enrolled to date, with 19 evaluable for toxicity and 13 for response assessment at D +100. The median age is 61 (47 - 69). The median time for engraftment for ANC ≥ 500 and plts ≥ 20, was 10 days. The median length of stay (LOS) was 18 days (16 – 21 days). 12 patients required a median of 2 units of PRBC and 16 patients required a median of 1 platelet transfusion. PRBC and PLT transfusions as well as LOS are not significantly different to what has been observed at our institution with MEL 200 (2 PRBC, 2 RD PLT transfusions, and 15 days LOS, respectively). All patients responded including: 77% ≥ VGPR and 54% nCR, CR, or sCR. The most common grade ≥ 3 toxicities were neutropenic fever (n = 11), mucositis (n = 9), and hypophosphatemia (n = 7). Three patients developed reversible transaminitis. One patient developed Clostridium difficile colitis and Klebsiella pneumonia UTI. Another patient developed E. coli UTI. No cases of VOD or interstitial pneumonitis were observed. There were no treatment related deaths and no re-admissions post discharge. Conclusion: BuMelVel proved to be an effective preparative regimen with ≥ VGPR and nCR/CR/sCR of 77% and 54%, respectively, as compared to responses reported with MEL/BTZ (70% and 32%, respectively); and to MEL 200 alone (43% and 11%, respectively) by Roussel et al. Furthermore, BuMelVel had an acceptable toxicity profile without any cases of VOD or interstitial pneumonitis, and mucositis/infections incidence and severity are comparable to our institutional experience with MEL 200. Therefore, the regimen of BuMelVel may lead to improvements in PFS and OS, critical criteria to improve the outcomes of patients with MM. These promising results will be further evaluated in a planned Phase III clinical trial with MEL 200. Disclosures: Rodriguez: Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. Kaufman:Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Speakers Bureau.

9132 Background: Depression and decreased quality of life (QL) develop frequently in BMT patients. We conducted a prospective randomized trial to assess whether pretreatment of BMT patients with th...

6507 Background: Management of adult ALL patients who relapse is challenging due to highly drug resistant disease and frequent residual therapy-induced toxicity. The increasing success of Salvage 1...

8033 Background: The survival of adult BL has improved with intensification of multiagent chemotherapy, although 2-year survival rates remain

Abstract 3331 Poster Board III-219 Introduction Current data suggests that recipient age above 50 is associated with an inferior outcome after myeloablative allogeneic stem cell transplantation (SCT). Overall survival (OS) of 31%, and transplant related mortality (TRM) of 17% at 100 days have been reported in this population (Ditchkowski, et al 2005; Yanada, et al. 2004). Encouraging results are observed with non-myeloablative conditioning regimens. However, for patients with a high relapse risk, this approach may not be sufficient to achieve long term disease control. In these cases, a reduced toxicity, yet ablative stem cell transplantation (RT-SCT) may give adequate time to the transplanted cells to mature and mount an immune-mediated antitumor response. This study evaluated the outcome after RT-SCT using a conditioning regimen consisting of intravenous busulfan (Bu) and pentostatin (Pent). Methods Consented adult patients up to 70 years with a fully-matched related (MRD) or unrelated donor (MUD) were screened for enrollment. Conditioning consisted of Bu 1.6 mg/kg every 12 hours days -7 to -4, and Pent 4 mg/m2 on day -3 and -2 prior to stem cell infusion on day 0. GVHD prophylaxis was methotrexate 10 mg/m2 on day 1, and 5 mg/m2 on days 3, and 6. Tacrolimus was started on day -2, and then tapered over 1 month after day +100. Characteristics Twenty six patients were analyzed. Male to female ratio was 1:1. Stem cell source was from MRD in 15 patients and MUD in 11. Median age was 62, with 92% of patients being older than 50 years. Indications for treatment were AML (35%), MDS (42%), Refractory CLL (23%), Relapsed NHL (12%), and Philadelphia (+) ALL (4%). All AML patients were high risk either due to poor cytogenetic, transformation, or relapse and only two of them were transplanted in first complete remission. MDS patients were RAEB (36%), secondary MDS (36%), or multilineage dysplasia (18%). Two patients had prior autologous transplants. Results No graft failure was observed. All patients achieved neutrophil (NEU) engraftment. Two patients expired prior to platelet (PLT) engraftment. Median engraftment days for NEU and PLT were 13 days. At a median follow up of 25 months, the OS and progression free survival for the entire group was 40% and 38% respectively. The OS in the MRD group was 58%. TRM at 100 days was seen in one patient (4%) due to veno-occlusive disease (VOD). Limited chronic GVHD was the most common observed toxicity (54%), followed by diarrhea (30%) and mucositis (23%). Mucositis was mainly grade 1 (8%) and grade 2 (8%). No grade 3 mucositis was observed. There was only one case of VOD and one case of acute GVHD. Conclusion To our knowledge, this is the first report of a RT-SCT using BuPent. This study demonstrates the efficacy of the regimen in patients older than 50 years. No graft failure was observed and the regimen related toxicity was acceptable in this high-risk population. The overall survival of 40% at a median follow up of 25 months compares favorably with prior reports of myeloablative allogeneic stem cell transplatation in patients older than 50 years. This regimen provides an exciting opportunity to extend the benefits of allogenic transplant to an older population, and warrants replication with larger controlled trials. Disclosures Rodriguez: Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vesole:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Millenium: Speakers Bureau; Centocor Ortho Biotech: Speakers Bureau.

Abstract 2081 Poster Board II-58 AZD6244 is an orally bioavailable small molecule inhibitor of the MEK kinase. MEK is downstream of the RAS/RAF pathway, which is activated by mutations occurring in RAS as well as mutations and/or overexpression of upstream receptor tyrosine kinases such as FLT3 and c-KIT in AML. In addition, elevated levels of phosphorylated-ERK (p-ERK), the only known substrate of MEK, have been demonstrated in >75% of patients(pts) with AML, and MEK inhibition of primary AML cells in vitro results in growth arrest. AZD6244 was well tolerated in phase I trials in advanced solid tumors and had a favorable pharmacokinetic profile; the recommended phase II dose was 100mg twice daily. We hypothesized that in AML, a MEK inhibitor would lead to inhibition of RAS-mediated signal transduction, with subsequent antiproliferative effects and inhibition of the leukemia clone. We report our experience with the first clinical trial utilizing a MEK inhibitor in advanced AML. Methods: 47 pts were enrolled on a Phase II multicenter study of AZD6244 in relapsed/refractory AML. Median age was 69 years (range, 26-83 yrs) with 57% males. ECOG performance status at baseline was 0, 1 and 2, respectively, in 12, 27 and 8 pts. 14 pts (30%) were previously untreated for AML and >60 yrs; 11 of these pts had received prior therapy for an antecedent hematologic disorder (AHD); 1 had therapy-related AML (t-AML) and only 2 pts (4%) had previously untreated de novo AML. 6 pts (13%) had AML in first relapse, 14 (30%) had AML beyond first relapse, and 13 (27%) had primary refractory disease. 4% had good risk cytogenetics, 28% intermediate risk, 49% poor risk, and 19% had other or unknown cytogenetics. Overall, 53% had AML that had evolved from an AHD and/or t-AML. Ten pts had a FLT3 ITD or TKD, 36 had no FLT3 mutation detected, and FLT3 mutational status was unknown in 1. Median number of prior therapies for AML and/or MDS was 2 (range, 0-6). AZD6244 was given at 100mg twice daily without interruption; cycles were repeated every 28 days. Dose modifications and/or delays occurred for grade 3&4 non-hematologic toxicities, or prolonged grade1&2 toxicities. Peripheral blood and/or marrow samples were obtained at baseline for mutational analysis (RAS/c-KIT/FLT3), and at serial time points to measure p-ERK. Results: Daily AZD6244 was tolerable. 42 pts are evaluable for efficacy and safety. Median number of cycles administered was 1 (range, 1-9). 19 pts (40%) received ≥2 cycles. 4 pts required dose reduction. The most common drug-related toxicities were grade 1&2 diarrhea, nausea, fatigue and vomiting, occurring in 43%, 36%, 31% and 24%, respectively. Grade 3&4 adverse events possibly related to AZD6244 included fatigue, nausea and dehydration, occurring in 7%, 5% and 5%, respectively. 4 pts had a minor response (defined as >50% decline in peripheral blood and/or marrow blasts lasting 4 weeks). 2 additional patients also had >50% decline in marrow blasts but did not have a follow up confirmatory biopsy. In 1 of these pts, the decline in blasts was associated with sustained improvement in platelets (>100K/uL) lasting 4 months. 6 additional pts had evidence of disease stabilization, lasting a median of 34 days (range, 21-222+ days). Analysis of p-ERK by flow cytometry has just been intiated, and in the first 3 pts analyzed, baseline p-ERK levels were low, and none of these pts responded. In contrast, p-mTOR levels (downstream of the PI3 Kinase pathway) were significantly elevated in these same pts. Conclusions: Administration of the oral MEK inhibitor AZD6244 is feasible in AML. Modest evidence of antileukemic activity has been observed, consistent with the predicted cytostatic activity of this class of drugs. Analysis of the effect of AZD6244 on p-ERK and signaling intermediates of the PI3 Kinase pathway such as p-mTOR is ongoing. Given its modest toxicity profile, AZD6244 should be investigated further in combination with drugs that target other critical signaling pathways and/or dysregulated transcriptional pathways in AML. Sponsored by NCI grant NO1-CM-62201 Disclosures: No relevant conflicts of interest to declare.

Abstract 2267 Poster Board II-244 Introduction: Both acute and delayed nausea and vomiting are a major problem for patients undergoing highly emetic high dose preparative regimens prior to hematopoietic stem cell transplant (HSCT). Aprepitant (APR) is an NK-1 antagonist FDA approved for the prevention of N/V due to standard dose highly and moderately emetogenic chemotherapy. While several small Phase II studies have suggested its benefit in HSCT, no completed prospective comparisons have been reported. In addition as APR is known to interact with cytochrome P450 isoenzymes involved in the bioactivation of high dose cyclophosphamide, and may interfere with etoposide pharmacokinetics, its impact on regimen related toxicity and long term survival post transplant is unknown. Patients and Methods: We performed a randomized (1:1 randomization) blinded Phase III trial to determine the safety and efficacy of APR for N/V due to ablative preparative regimens. Patients received either placebo (PBO) or oral APR 125mg PO day 1 then 80mg daily during and for 3 days after the preparative regimen was completed, in addition to oral ondansetron 8 mg PO q 8hrs + IV dexamethasone daily during and for 1 day after the preparative regimen. Only PRN lorazepam was permitted for nausea. Due to a known drug interaction between APR and dexamethasone, patients also received blinded dexamethasone doses of 10mg on the placebo arm and 7.5mg on the APR arm. Patients were stratified based on gender, and patients with heavy ETOH use were excluded. Clinical evaluations were performed daily during therapy with the primary endpoint being a CR, defined as: no emesis and no or mild nausea [less than grade (gr) 3 using CTC 2.0 criteria]. Other endpoints included; major response (MR): 1 episode of emesis or moderate nausea; minor response (mR): 2–4 episodes of emesis; and failure (F) : >4 episodes of emesis. Major efficacy (ME) = CR + MR. Other analyses performed included subjective nausea based on a 100 mm visual analog scale (VAS) with 0 = no nausea; amount of PRN antiemetics used to control breakthrough N/V and no emesis all days.. Safety analyses performed included time to engraftment, 30 day survival and progression free survival (PFS) and overall survival (OS). The study began 9/20/04 and completed enrollment 7/18/08. The study was powered (90 pts per arm) to detect a difference of 20 % between the two groups with a significance level of 0.05 using a two-sided t-test. The 181 randomized patients were balanced with respect to age, weight, donor source and h/o N/V with prior chemotherapy. Patients received one of 5 ablative prep regimens: CY/TBI/VP16 (36), CY/TBI (79), IV BU/CY (14), PO BU/CY (34), and BCV(16) Two pts never proceeded to transplant so only 179 pts are eligible for analysis. Ten pts (6 APR/4 PBO) failed to complete the study; data were analyzed as intent to treat. Results: Efficacy: There was a difference in CR rate (primary endpoint) in favor of APR: 81.9% vs 65.8 % for those receiving PBO with 48.9% vs 14.6% respectively meeting this endpoint for the entire study period (p Conclusions: When used daily up to 10 days with ablative preparative regimens, aprepitant significantly improved control of acute and delayed regimen-related N/V with a major impact on emesis rates. It appears safe for this indication with no impact on WBC and PLT engraftment as well as PFS and OS. Disclosures: Stiff: Merck: Research Funding. Off Label Use: Aprepitant in BMT setting.

Abstract 1034 Poster Board I-56 Background: Poor-risk groups with AML – defined as those above age 50, those with secondary or treatment-related disease, and individuals relapsing after or refractory to initial therapy – have a very disappointing response to therapy and a dismal overall survival, on the order of 6 months. Therapeutic options are limited by age, comorbidities and toxicities from prior treatment. Hypomethylating agents, such as Azacitidine (AZA) may induce remission in up to 20% of patients. We have previously published a pilot study of a regimen combining AZA and low-dose gemtuzumab ozogamicin (GO) for the treatment of newly diagnosed, elderly patients with AML or high-risk MDS. (Leuk Lymphoma. 2008:49:2141-7) The combination produced a 70% CR/CRi rate, a median OS of 10 months and formed the basis of a national cooperative group trial in this select population. Based on these results, our institution broadened the use of this regimen to patients not otherwise eligible for standard therapy or a clinical trial, including patients with relapsed or refractory disease. We have retrospectively analyzed the clinical characteristics and outcomes of 56 patients treated with this regimen at our institution between September 2006 and July 2009. Methods: With IRB consent, all off-study patients with AML and MDS as well as those with relapsed/refractory AML were included in this analysis. Patients were included if they received at least one full cycle of AZA at a dose of 75mg/m2 SQ or IV daily for seven days followed by GO 3mg/m2 IV on day 8. A second cycle could be given after a day 15 bone marrow (BM) if there was no evidence of a CR or aplasia. Patients could receive consolidation therapy with the same regimen for one or more additional cycles and/or could continue on monthly maintenance therapy with single-agent AZA. Results: Patient characteristics: Between September 2006 and May 2009, a total of 56 patients received the regimen, 26 (46%) for the treatment of relapsed or refractory disease and 30 (54%) as first-line therapy. Most were treated for AML, but 11 (20%) had high-risk MDS, including three with CMMoL. The average age of patients at the time of treatment was 63 yrs, range of 23-85 yrs. Following induction, 17 patients received AZA alone as monthly maintenance therapy and nine were treated with allogeneic transplantation. The treatment-related mortality was 10% (n=6). Grade 3 or 4 non-hematologic toxicities, primarily infection or infusion reactions related to GO, were recorded in 17 patients (30%). Response rate/Overall survival Of the 56 patients, 15 (27%) achieved a CR or CRi. An additional seven patients cleared their peripheral blood blasts or had hematologic improvement but did not have BM documentation of remission. CR or CRi was achieved in five of 22 patients (22%) with poor-risk cytogenetics and seven of the 24 (29%) patients who had therapy-related disease or disease that had evolved from pre-existing hematologic malignancy. The median OS was 21 weeks (range: 1-118). In patients who achieved a CR or CRi, the median OS was 40 weeks (range: 9-118). Most notably, seven of 26 patients (26%) with relapsed or refractory disease achieved a documented CR or CRi – including two patients with primary refractory disease and two who had relapsed after allogeneic transplantation. The median OS of these seven patients was 40 weeks (range: 9-118). Maintenance therapy with monthly AZA monotherapy was administered to 17 patients, 11 of whom had achieved a documented CR or CRi. The mean number of months of maintenance therapy was four; 8 received 5-10 cycles. Patients receiving maintenance therapy after achieving CR or CRi had a median OS of 45 weeks (range 20-118). Conclusions: The combination of AZA and low-dose GO produced a CR/CRi of 27% and a low TRM in an extremely poor-risk group of patients with AML and high-risk MDS. Responses were seen in patients with primary refractory disease and those who relapsed following allogeneic stem-cell transplant. Patients who were able to achieve a CR or CRi appeared to benefit from several months of maintenance AZA and had a median survival of nearly one year. Based on these results we are opening a prospective trial of this regimen for patients with relapsed or refractory disease with responders continuing on azacitidine indefinitely or proceeding to allogeneic transplantation. Disclosures: Off Label Use: I will describe the use of Azacitadine for acute myeloid leukemia. Smith:Celgene: Speakers Bureau. Nand:Pharmion/Celgene: Consultancy, Research Funding, Speakers Bureau.

Abstract 43 We have previously shown that TNF Receptor 1 (TNFR1) levels early after myeloablative hematopoietic cell transplant (HCT), especially following unrelated donor (URD) HCT, predict later graft-versus-host disease (GVHD), non-relapse mortality (NRM), and overall survival (OS). Given this data we hypothesized that augmenting standard GVHD prophylaxis with the TNF-inhibitor etanercept would protect against GVHD and NRM while improving survival. We therefore conducted an IRB-approved Phase II trial at two centers to determine whether prophylactic TNF blockade with etanercept decreases the rates of acute GVHD and day 100 NRM seen after high-risk allogeneic matched (n=68, 71%) or single antigen mismatched URD (n=25, 26%) or single antigen mismatched related donor (RD) (n=3, 3%) HCT. Follow-up data are available for 96/100 patients (pts) enrolled between 2005 and 2009. HLA matching used high-resolution DNA-based techniques for HLA-A, B, C, and DR. Patients received tacrolimus, methotrexate (5 mg/m2 on days 1, 3, 6, 11) and etanercept (0.4 mg/kg, max 25 mg) twice weekly from the start of conditioning to day 56. All pts received myeloablative regimens; either TBI/cyclophosphamide (TBI, n=29), fludarabine and 12.8 mg/kg IV busulfan (FluBu4, n=31) or other myeloablative chemotherapy regimens, either BCNU/etoposide/cyclophosphamide or busulfan/cyclophosphamide (BCNU/Busulfan, n=36). The median age of the pts was 45y (range 2-61y). To determine whether the administration of etanercept effectively reduced post-transplant TNFR1 levels we compared day 7 post-transplant TNFR1 levels in the 96 study pts to 132 control pts who received standard GVHD prophylaxis of tacrolimus/methotrexate and were matched for age, conditioning regimen, degree of HLA-match, and disease status. The median day 7 TNFR1 levels in study pts was 2518 pg/ml, significantly lower than the median day 7 level of 3529 pg/ml in control pts (p We have evidence that etanercept effectively lowers TNFR1 levels at day 7 post-transplant, a time point associated with GVHD and HCT outcomes. However, the degree of TNFR1 level reduction appears to depend in part on the conditioning regimen. The median day 7 TNFR1 levels were statistically different across conditioning regimens, and those with low TNFR1 levels have improved outcomes (FluBu4>BCNU/Busulfan>TBI). In fact, for the FluBu4 pts in particular, preliminary data suggest superior outcomes, including low rates of GVHD and remarkably high 2 year OS for high-risk transplant pts, without use of thymoglobulin. After highly intense conditioning regimens, such as TBI-based, TNFR1 levels remained high despite TNF reduction with etanercept and outcomes are similar to those expected with standard GVHD prophylaxis. With the less toxic, but still myeloablative FluBu4 conditioning regimen, however, the addition of etanercept appeared to lower TNFR1 levels to levels that were protective against NRM. Thus, the effectiveness of etanercept may depend on the conditioning regimen, warranting a randomized trial to explore this interaction further. Disclosures: Off Label Use: Etanercept - for GVHD prophylaxis.

The Nature Conservancy takes a strategic and systematic approach to conservation planning. Ecoregional assessments are used to set goals and identify geographical priorities, and Conservation Action Planning is used to develop strategic plans for conservation areas. This study demonstrates how these planning processes were applied at the seascape scale based on a case study of Kimbe Bay, Papua New Guinea. Conservation Action Planning was used to identify key threats and strategies, and systematic conservation planning (similar to that used for ecoregional assessments) was used to design a network of marine protected areas to be resilient to the threat of climate change. The design was based on an assessment of biodiversity and socio-economic values, and identified 14 Areas of Interest that meet specific conservation goals. A detailed community-based planning process is now underway with local communities that own and manage these areas to refine and implement the marine protected area network.

8510 Background: PTLD has a reported 3-year (yr) overall survival (OS) of 35–40% (Leblond, JCO 2001). The impact of rituximab (RTX) on the prognosis or outcome of PTLD is not known. Methods: We examined the clinical features, treatment, and outcomes among a large population-based cohort of SOT-related PTLD patients (pts) at 4 Chicago institutions (1/98–2/08). Prognostic factors were evaluated in univariate and Cox proportional hazards regression for survival. Results: 81 PTLD pts were identified (SOT: 47 kidney ± pancreas, 4 pancreas, 17 liver, 8 heart, 5 lung) with median age at diagnosis (dx) of 48 yrs (range 20–72). Median time from SOT to PTLD was 42 months (mo) (range 1–216 mo). PTLD dx (per WHO) were 55 monomorphic, 22 polymorphic and 4 plasmacytic, while 42 were EBV+ and 30 EBV-negative (9 unknown). 74% of pts (60/81) were treated with rituximab ± chemotherapy (and reduction of immune suppression). With 38-mo median followup for all pts, 3-yr progression-free (PFS) was 58% and 3-yr OS 62%, despite 16% of pts dying ≤ 6 weeks from dx. Most relapses (30/32) occurred ≤ 12 months from dx. Pts receiving RTX as part of therapy had 3-yr PFS of 69% and OS 71% (vs 21% (p=0.0002) and 33% (p=0.001), respectively, without RTX). Univariate analysis identified prognostic factors for PFS/OS (all 1 EN site, 4) marrow involvement, 5) CNS disease and 6) RTX as part of initial therapy. Neither histology nor EBV status predicted outcome. On multivariate analysis, 4 factors remained significant ( Table 1a ). Further, a survival model based on 3 factors was constructed ( Table 1b ). Conclusions: This study represents the largest PTLD report in RTX-treated pts. We are the first to identify the prognostic significance of low albumin and a low PTLD relapse rate beyond 1 yr (6.3%). Further, it appears that the introduction of RTX has improved the survival of PTLD. In addition, clinical factors at dx identified pts with markedly divergent outcomes. [Table: see text] [Table: see text] No significant financial relationships to disclose.

DNA hypermethylation of promoter-specific CpG islands has been implicated in the pathogenesis and progression of myelofibrosis (MF). We have evaluated Decitabine, a DNA methyltransferase inhibitor in patients (pts) with MF, including primary MF (PMF), and MF arising after polycythemia vera or essential thrombocythemia (post-PV or post-ET MF). This was a multicenter, single stage Phase II trial, with a planned accrual of 20 patients. The regimen would be deemed worthy of further investigation if ≥ 5 pts responded. Eligibility criteria included myelofibrosis associated with anemia (hemoglobin 50% increase in platelet levels) have also been observed. Median time to response was 2 cycles (range 1–6); median duration of response was 5 months (range 2–15). Two pts are maintaining their responses at 2 and 14 months. All responders who developed disease progression did so while off therapy. Analysis of the effects of decitabine on CD34+ cells revealed a 61% reduction (p1%) than non-responders at baseline and post-therapy (p Conclusions: Low dose SQ decitabine is feasible, has clinical activity and deserves further investigation in myelofibrosis. Myelosuppression is common and requires close monitoring. A decline in circulating CD34+ progenitor cells that persists into cycle 2 of therapy may serve as a novel biomarker that predicts response to decitabine in myelofibrosis.

The end of the Cold War and major systemic changes over the past two decades in the distribution of power require a re-examination of United States national security strategy. Over its history, the U.S. has pursued strategies based on isolationism, Hemispheric defense, balance of power and collective security, as well as containment of the Soviet Union during the Cold War. This essay assesses which strategy or combination of strategies will best protect U.S. physical security in the post-Cold War period.

Platelet transfusion refractoriness following allogeneic bone marrow transplantation usually stems from HLA alloimmunization. However other platelet antigens may serve as targets of alloimmune reactivity. A 24-year-old Palestinian male with atypical CML in chronic phase underwent matched unrelated donor bone marrow transplant from a 39-year-old female, HLA-A, B, C and DR allele level matched donor. Conditioning was with busulfan 0.8mg/Kg IV q6 hours day -8 through -4, cyclophosphamide 60mg/Kg IV daily day -3 & -2 and rabbit anti-thymocyte globulin 1.5mg/Kg IV daily day -5 & -4. Graft versus host disease prophylaxis was with mini-dose methotrexate and tacrolimus, with filgrastim given for hematopoietic reconstitution. The cell dose was 1.86x106 CD34+ cells/Kg recipient body weight (3.66x108 mononuclear cells/Kg). Neutrophil engraftment occurred on day +14, and was complicated by a diffuse purpuric skin rash, with hypoxia and pulmonary infiltrates which resolved with corticosteroid therapy. His post-transplant course was also complicated by severe, transfusion refractory thrombocytopenia (to random donor pools, apheresis and crossmatched platelet units) starting on day +5 with platelet counts of 98% donor chimerism. As his immunosuppression has been tapered over time, the antibody titer has declined (Fig) as has his platelet transfusion requirement (41 doses transfused between day 31 and 120). However he remains dependent upon directed donor platelet transfusions from his CD36 negative family members at 120 days from transplant. The CD36 negative phenotype is rare in Caucasians, however, platelets from about 5% of individuals of Asian or African descent lack CD36. DNA sequencing to determine CD36 mutations in this patient is underway. We hypothesize that this patient developed a host vs. graft humoral response against donor derived and transfused platelets resulting in sustained severe thrombocytopenia. Patient serum CD36 antibody titers following transplant Patient serum CD36 antibody titers following transplant