ALBERT

Description: The origin and age of topography along the west Greenland margin is a matter of continued debate. Evidence for tectonically driven Neogene uplift has been argued from interpretations of offshore seismic surveys, onshore fission-track data and inferred episodes of cooling. Here, analysis of seismic reflection profiles and 1D modelling of exploration wells along the Greenland margin of Davis Strait demonstrate that the data are consistent with a model of ancient continental topography affected by late Cretaceous–early Palaeocene rifting followed by thermal subsidence where offshore Neogene tectonic uplift is not required. This interpretation for the offshore evolution of the west Greenland margin has implications for the adjacent onshore evolution and for other continental margins developed throughout the Atlantic–Arctic rift system.

Description: We use an empirical statistical model to demonstrate significant skill in making extended-range forecasts of the monthly-mean Arctic Oscillation (AO). Forecast skill derives from persistent circulation anomalies in the lowermost stratosphere and is greatest during boreal winter. A comparison to the Southern Hemisphere provides evidence that both the time scale and predictability of the AO depend on the presence of persistent circulation anomalies just above the tropopause. These circulation anomalies most likely affect the troposphere through changes to waves in the upper troposphere, which induce surface pressure changes that correspond to the AO.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baldwin, Mark P -- Stephenson, David B -- Thompson, David W J -- Dunkerton, Timothy J -- Charlton, Andrew J -- O'Neill, Alan -- New York, N.Y. -- Science. 2003 Aug 1;301(5633):636-40.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Northwest Research Associates, 14508 NE 20th Street, Bellevue, WA, 98007, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12893941" target="_blank"〉PubMed〈/a〉

Description: Cyclic sedimentary deposits link stratigraphic sequences that are now geographically distant but were once part of the same depositional environment. Some of these sequences occur at periods of 2 to 20 million years, and eustatic sea-level variations or regional tectonic events are likely causes of their formation. Using numerical modeling, we demonstrate that small-scale mantle convection can also cause the development of stratigraphic sequences through recurrent local and regional vertical surface movements. Small-scale convection-driven stratigraphic sequences occur at periods of 2 to 20 million years and correlate only at distances up to a few hundred kilometers. These results suggest that previous sequence stratigraphic analyses may contain erroneous conclusions regarding eustatic sea-level variations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Petersen, K D -- Nielsen, S B -- Clausen, O R -- Stephenson, R -- Gerya, T -- New York, N.Y. -- Science. 2010 Aug 13;329(5993):827-30. doi: 10.1126/science.1190115.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Earth Science, Aarhus University, DK-8000 Aarhus C, Denmark. kenni@geo.au.dk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20705857" target="_blank"〉PubMed〈/a〉

Description: Abstract 3933 Background Ofatumumab is a novel fully humanized anti-CD20 monoclonal antibody with antigenic target distinct from rituximab and enhanced antibody dependent cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) with single agent activity in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), including heavily pretreated patients. The immunomodulatory agent (IMID) lenalidomide has been shown to induce T cell and NK cell activation and in vitro enhances rituximab induced killing of B-CLL cells via NK cell-mediated and monocyte-mediated ADCC. We hypothesized that the sequential treatment of patients with ofatumumab and lenalidomide would provide optimal pharmacodynamic interaction and be active in R/R patients previously treated with rituximab containing regimens. Methods Eligibility criteria included confirmed diagnosis of R/R CLL meeting criteria for treatment, prior therapy containing rituximab, age≥ 18 years, ECOG performance status ≤ 2 adequate hepatic, renal and bone marrow function and willingness to comply with the required birth control measures. Patients were excluded if they had been previously exposed to any of the experimental agents, had active hepatitis B or carried HIV. Treatment consisted of ofatumumab 2000 mg (300 mg on the first cycle) intravenously on day 1 and lenalidomide 10 mg (5mg on the first cycle) on days 8–28. Treatment was administered for up to 6 cycles of 28 days duration. Patients received prophylaxis with acyclovir and trimethoprim + sulfamethoxazole. Toxicity was assessed according to CTC v.4.0 and response was evaluated following the 2008 National Cancer Institute Working Group criteria. Results Seventeen patients have been enrolled and 14 have sufficient follow-up to be assessed for response. Median age of patients was 65 years (range 51–80). Median number of prior lines of therapy was 2 (range 1–4) and median baseline white blood cell count was 75,000/mm3. The proportions of cases with unmutated IgvH chain and positive ZAP-70 expression were 15/17 (88%) and 13/16 (81%), respectively. There were 4/16 (25%) cases with del17p and 4/16 (25%) with del11q detected by fluorescence in situ hybridization (FISH). Thirteen cases (76%) were refractory to, or had relapsed after treatment containing a purine analogue. The most frequent adverse event (AE) 〉 Grade 1 was tumor flare reaction (TFR), seen in 8/14 (57%) patients and infusion reactions seen in 6/14 (43%) patients. Four patients with TFR were managed successfully with non-steroidal anti inflammatory agents while 4 required glucocorticoids allowing continuation of therapy in all patients. The most common Grade 3+4 AE was neutropenia (11/14, 79%) although it was associated with infection in only 1 episode. One subject had early discontinuation due to toxicity (elevation in AST and ALT precluding further administration of ofatumumab). The majority of patients (11/14, 79%) required dose reduction or could not have the planned dose increase of lenalidomide after cycle 1 due to hematological toxicity. Overall 6/14 (43%) had objective response and 3/14 (21%) had stable disease for an overall clinical benefit in 64% of patients. All patients with TFR〉 Grade 1 had at least stable disease. Conclusion Intracycle sequential ofatumumab plus lenalidomide is well tolerated in advanced, high-risk CLL except for high rate of TFR and neutropenia without infection. Sequential ofatumumab and lenalidomide may be associated with higher rate of TFR than concomitant therapy. Approximately half the patients treated with this combination will obtain disease control. Further investigation is warranted in earlier lines and/or for more prolonged therapy. Disclosures: Costa: GSK: Research Funding. Off Label Use: Lenalidomide for treatment of CLL.

Description: Abstract 1198 Risk stratification of plasma cell neoplasms (PCNs) has become an integral part of clinical management along with the rapid advances in treatment. Cytogenetics is widely performed at diagnosis but has a low abnormality detection rate due to poor proliferation of plasma cells (PCs) in culture and inability to identify cryptic translocations. Conventional interphase FISH improves detection sensitivity, but lacks specificity since the percentage of PCs is diluted by the large number of normal bone marrow cells due to the indiscriminative analysis of all cells by FISH. The International Myeloma Working Group recommends all FISH tests for myeloma be PC specific by either PC enrichment or identifying PCs by cytoplasmic immunoglobulin staining (cIg FISH). However, the real benefits of cIg FISH compared to conventional FISH have never been demonstrated in a controlled study. In this objective comparative study, 75 paired samples from patients with PCNs were analyzed concurrently by conventional FISH and cIg FISH with probes for t(4;14), t(11;14), t(14;16), -13/13q (RB1/LAMP1), 17p- (TP53) and CEP3. For conventional FISH, a minimum of 200 nuclei were scored per probe set. For cIg FISH, 100 cIg positive cells were scored per probe with a minimum of 25 cIg+ cells required for conclusive reporting. In this study, 51/75 cases met the above criteria for direct comparison (see Table). cIg FISH results demonstrated an improved overall detection rate [-13/13q: 53% vs. 45%; 17p-: 14% vs. 12%; t(11;14): 25% vs. 24% and t(4;14): 14% vs.12%]. Impressively, cIg FISH quantitatively identified a much higher proportion of abnormal PCs in all cases. The median % of abnormal PCs with all probes was 〉50% by cIg FISH but no more than 10% by conventional FISH. The abnormal PCs detected by cIg FISH were 〉90% of cIg+ cells in 18 cases with at least one probe. In contrast, the abnormal PCs detected by conventional FISH were

Description: Abstract 4061 Introduction The rate of relapse in multiple myeloma (MM) remains high despite novel therapies such as the proteasome inhibitor bortezomib. Histone deacetylase (HDAC) inhibitors (panobinostat and vorinostat) in combination with bortezomib have demonstrated activity in patients (pts) with relapsed and refractory MM. However, pan-HDAC inhibitors target multiple HDAC enzymes, including HDAC6 and Class 1 enzymes, and are associated with adverse effects such as severe fatigue, nausea, vomiting, diarrhea, and myelosuppression. HDAC6 regulates acetylation of cytoplasmic tubulin, an essential component of aggresome formation in an alternative pathway to the proteasome to remove unfolded or misfolded proteins. Therefore selective inhibition of HDAC6 may lead to efficacy in MM with an improved safety profile. Rocilinostat is a novel selective inhibitor of HDAC6 with 11-fold selectivity over Class 1 HDACs. Preclinical results in models of MM demonstrate synergy between bortezomib and rocilinostat (Blood 119(11):2579-89) and a superior safety profile compared with pan-HDAC inhibitors. We examined the pharmacokinetics, pharmacodynamics, safety, and preliminary activity of rocilinostat, alone and in combination with bortezomib and dexamethasone, in pts with relapsed or relapsed/refractory MM. Methods Patients with relapsed or relapsed/refractory MM, previously exposed to both proteasome inhibitor and immunomodulatory agents, were enrolled in an ongoing, 3-part, phase I/II, single-arm, open-label study. A group sequential dose-escalation design was used to identify optimal dosing of rocilinostat alone (Part 1) and in combination with bortezomib and dexamethasone (Part 2), followed by evaluation of the objective response rate and safety of the combination (Part 3). In Part 1, pts received single oral daily doses of rocilinostat for 5 consecutive days during Weeks 1 (Days 1–5) and 2 (Days 8–12) every 3 weeks, with a starting dose of 40 mg and planned escalation to 80, 160, 240, 360, and 480 mg. Part 2 began in parallel after completion of the third monotherapy cohort, with a starting dose of 40 mg rocilinostat plus bortezomib 1.0 mg/m2twice weekly (Days 1, 4, 8, and 11) and 20 mg dexamethasone given on the day of and day after each bortezomib dose. Pharmacokinetics were assessed on Days 1, 4, 8, 11 and 15 and pharmacodynamics in blood mononuclear cells were measured on Day 1. Patients received up to 6 cycles of therapy, or more if experiencing clinical benefit. Available data are for the first 4 monotherapy cohorts (40, 80, 160, 240 mg) and the initial 3 pts in the first combination cohort (16 pts total). Results Of the 16 pts, 13 were treated with monotherapy and 3 with combination. Median age was 70 yrs (range: 51–79), and 56% of pts were male. The majority of pts were either white (8, 50%) or black (7, 44%). Fourteen pts had relapsed/refractory MM and 2 had relapsed disease; 88% of pts received ≥ 3 prior treatments. Patients received a median of 2 cycles of rocilinostat (range: 1–10). Monotherapy was well tolerated with no dose-limiting toxicities (DLTs) and mostly grade 1–2 adverse events (AEs). The most common AEs with monotherapy were elevated creatinine, diarrhea, fatigue, and upper respiratory tract infection (n=3 each). Grade 3/4 treatment-related AEs on monotherapy occurred in 1 pt (grade 3 anemia). In the first combination cohort, 1 pt had a DLT (elevated amylase). Five monotherapy pts had stable disease. One combination pt with relapsed/refractory disease had a 26% reduction of serum M protein at Cycle 2. Rocilinostat was rapidly absorbed (Table) and displayed approximately dose-linear pharmacokinetics with no accumulation of drug. Maximal levels of acetylated tubulin in peripheral blood were observed 1 hr post dose. The magnitude of the signal increased with dose and exposure (Table), with all cohort 3 pts having at least a doubling of acetylated tubulin levels. Conclusion Preliminary results from this first clinical evaluation of rocilinostat suggest that selective inhibition of HDAC6 with rocilinostat, alone or in combination with bortezomib and dexamethasone, may provide a well-tolerated treatment option for relapsed or relapsed/refractory MM. Updated data will be presented. Disclosures: Raje: Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding. Hari:Celgene: Consultancy, Honoraria. Vogl:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Research Funding; Otsuka: Consultancy; Acetylon: Research Funding. Jagannath:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Milenium Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees. Supko:Acetlon: Research Funding. Wheeler:Acetylon: Employment.