TPS7575 Background: Diffuse large B-cell Lymphoma (DLBCL), the most common lymphoid malignancy, is categorized by the putative cell of origin (COO) classification system into germinal center (GCB) and non-GCB subtypes. Both the immunomodulatory agent lenalidomide (L) and BTK inhibitor ibrutinib (I) have shown activity in the non-GCB DLBCL subtype as single agents and in combination with chemotherapy. Separate randomized phase III trials of RCHOP alone and +L or +I are ongoing in non-GCB DLBCL. Preclinical studies demonstrate L+I results in synthetic lethality in non-GCB DLBCL via interferon signaling (Yang et al, Cancer Cell, 2012), but no trials have evaluated the efficacy in newly diagnosed patients. We present the first "window of opportunity" trial to use targeted therapy (rituximab, R+L+I) alone prior to chemotherapy in newly diagnosed DLBCL. Methods: In this investigator initiated phase II trial, patients receive standard R dosing q 21 days (d), L 25mg po d1-10, I 560mg po d1-21, and after two 21d RLI cycles or earlier if disease progression will start RLI-EPOCH q 21d for 6 cycles, without maintenance therapy. EPOCH will be dose adjusted based on standard criteria, capped at level +2. L+I dosing may be reduced if significant toxicity criteria are met. Key eligibility criteria include histologically confirmed, treatment-naïve non-GCB DLBCL, age ≥ 18, adequate performance status and organ function, and measurable disease. COO will be determined via immunohistochemistry for eligibility, and NanoString (Scott et al, Blood. 2014) for confirmation. Patients will be restaged with PET/CT using Lugano criteria (Cheson et al, JCO 2014). The primary objectives are to determine the overall response rate after two RLI cycles and complete response rate after 6 RLI+EPOCH cycles. Secondary objectives include safety and survival outcomes. Exploratory objectives include evaluation of baseline and therapy induced changes in gene and protein expression, mutations, minimal residual disease monitoring, and immune cell subsets in comparison with clinical outcomes. The trial will accrue 60 patients, and employs Bayesian futility and toxicity monitoring rules. Clinical trial information: NCT02636322.
<p>In patients treated with vorinostat and everolimus, there was a longer median progression-free survival in patients with normal LDH compared to patients with high LDH (5.8 months, 4.4 - 7.2 vs. 1.6 months, 95% CI 1.3-1.9; P < 0.001).</p>
BEAM is considered standard HDC for ASCT for T-NHL. However, pts with relapsed or refractory (R/R) tumors have poor outcomes, underscoring the need for more active HDC regimens. Since 2007 we have developed a new HDC regimen of infusional gemcitabine (administered in a schedule that seeks to optimize its intracellular activation), busulfan and melphalan (Gem/Bu/Mel), exploiting inhibition of DNA damage repair (Nieto, BBMT 2012). Based on our preclinical observations that epigenetic modulation increases the cytotoxicity of Gem/Bu/Mel (Valdez, Exp Hematol 2012), in our recent trials we combined this regimen with vorinostat and azacitidine. We compared the outcomes of all patients with T-NHL treated with ASCT at our institution since 01/2007, either enrolled in trials of Gem/Bu/Mel ± vorinostat/azacitidine, or receiving BEAM. We analyzed 116 patients treated with Gem/Bu/Mel (N=32) (13 Gem/Bu/Mel, 11 vorinostat/Gem/Bu/Mel, 8 azacitidine/vorinostat/Gem/Bu/Mel) or BEAM (N=84) (see Table below). The Gem/Bu/Mel cohort included more patients with R/R tumors and was more heavily pretreated than the BEAM cohort.Tabled 1HIV +HIV-P valueMean Hyper CVAD cycles4.46.50.03Mean intra-thecal chemotherapy administrations (with Cytarabine 100mg, and Methotrexate 12mg)10.211.20.37Mean Rituximab doses3.34.20.8Mean LDH1140 u/l930 u/l0.62Mean Hemoglobin11.210.20.18Mean age39.2 years44.3 years0.25Mean baseline ECOG performance status1.31.60.12FISH for IgH/MYC or MYC rearrangement1190.59 Open table in a new tab Tabled 1Gem/Bu/Mel (N=32)BEAM(N=84)PAge, median (range)47 (16-67)59 (14-78)0.05Histology(%)Peripheral T-cell lymphoma (PTCL) NOS22190.6Angioimmunoblastic T-cell lymphoma (AITL)1634Anaplastic large-cell lymphoma (ALCL)ALK-196ALK+1913NK/T1610Hepatosplenic T-cell lymphoma (HSTL)68Other32Setting (%)CR128640.001Relapsed2826Refractory4410International Prognostic Index (PTCL NOS)4 (2-4)2 (0-4)0.01Disease-free interval (months)0 (0-79)3 (0-96)0.7No. prior regimens2 (1-3)1 (1-5)0.001No. prior relapses1 (0-3)0 (0-4)0.0006% PET at HDC (positive/negative)23 / 7710 / 900.06Follow-up, median (range) (months)21 (1-70)24 (1-102)0.2 Open table in a new tab Neither cohort had any treatment-related deaths. Among patients transplanted in CR1, the EFS and OS rates of the Gem/Bu/Mel cohort were both 89%, and of the BEAM cohort were 65% and 85%, respectively (P=NS). In the R/R setting, the EFS rates of the Gem/Bu/Mel and BEAM cohorts were 76% (median not reached) and 40% (median, 17 months), respectively (P=0.01) (Fig. 1A). The OS rates of the R/R Gem/Bu/Mel and BEAM cohorts were 75% (median not reached) and 60% (median, 41 months), respectively (P=0.3) (Fig. 1B). Cox regression models identified PET+ tumors at HDC [HR 3.14 (95% CI 1.3-7.5), P=0.01], the use of BEAM [HR 2.87 (1.15-7.18), P=0.02], and relapse/refractory setting [HR 2.09 (1.01-4.33), P=0.05] as independent adverse prognostic factors for EFS. Despite more adverse prognostic features, patients with R/R T-NHL treated with Gem/Bu/Mel (± vorinostat/azacitidine) presented superior EFS compared to a contemporaneous cohort of patients receiving BEAM.
Beach changes on the Hazaki coast extending between Kashima Port and Hazaki fishing port were investigated. Numerical simulation of beach changes and grain size changes were carried out, using the contour-line-change model considering the change in grain size (Kumada et al, 2005). In this area, fine sand is transported from outside to inside the wave shelter zone of the breakwater with the construction of Hazaki fishing port. Furthermore, 10.6×104 m3/yr of sand has been supplied from the Tone River and part of fine sand deposited inside the port. The mechanism of deposition of fine sand in the fishing port was well explained by the present model.
Field test of gravel nourishment was carried out on the Jinkoji coast surrounded by artificial headlands No. 6 and No. 7. After the preliminary nourishment using gravel of 7, 000m3 in 2005, 13, 000m 3 of gravel was additionally nourished. After the beach nourishment, extraordinary high waves attacked the coast in October in 2006. Despite these high waves, nourished gravel was stable to deposit in front of the seawall in a zone shallower than 2m below MSL, resulting in foot protection effect of the seawall without damaging the shellfish ground off the coast, where seabed materials are composed of fine sand.
The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade® ) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique β-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstroms macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid® ), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside. Keywords: Proteasome inhibitor, marizomib, bortezomib, NF-κB, multiple myeloma, pharmacodynamics, combination therapy
