ALBERT

Beschreibung: Background: A myeloproliferative neoplasm (MPN) is frequent underlying cause of splanchnic vein thrombosis (SVT). We reported that ruxolitinib, a JAK1/2 inhibitor, was safe in patients (pts) with MPN-associated SVT and effective in reducing spleen size at the planned primary analysis at 24 weeks (w) in an investigator-initiated phase II clinical trial (Pieri L, AJH 2016). Herein we present final long term follow up (FU) data. Methods. A total of 21 MPN-SVT entered the trial in 2012. Pts who completed the 24w core study and well tolerated the drug and had evidence of clinically-significant improvement were allowed to enter an extension phase up to w72, then entered a long term FU. The drug was provided by Novartis, that had no role in trial design nor in data analysis. Safety data were reported as cumulative incidence of adverse events (CTCAE v4.03). Clinical responses were defined according to ELN and IWG-MRT criteria. Results. Patients disposition. Eighteen patients were alive at last follow-up at a median of 5.5y, range 3.7-6.5y. Two pts died before w72 (hepatocarcinoma; unknown cause), 1 pt died at w252 (sepsis). Diagnosis of the 18 pts was: PMF 8 (44%), PV 5 (28%), ET 4 (22%), PET-MF 1 (6%). The DIPSS risk score of the 8 pts with PMF was low in 4 and intermediate-1 in 4. At last FU, 14 patients are still on ruxolitinib (78%), 10 pts still on clinical trial, 4 pts shifted to commercial drug. Four pts (22%) withdrawn treatment after w72 because of inefficacy, withdrawal of consent, unknown reasons, shift to observation only (1 each). Safety. Thirteen pts (72.2%) had adverse events; the median number of events per patient was 5 (range, 0-37). Five pts had G2 thrombocytopenia plus 1 pt G3 (28%), 9 had G2 anemia (50%), 1 had G2 neutropenia (6%). There were 4 non-hematologic G3 adverse events (22%), one drug-related (CPK increase) that resolved with dose reduction. Six pts developed G1-2 infections (33%), 4 had Herpes Zoster reactivation (22%), 1 developed second cancer (pheochromocytoma at w96; 6%). Efficacy. Spleen response (defined as percentage reduction of spleen length from left costal margin (LCM) from baseline value as by IWG-MRT criteria) was available in 16 of 18 pts on treatment. Of 8 pts who obtained spleen response at w72, 4 pts had a complete response, while the remaining 4 pts had a spleen reduction 〉50%. At last FU, 6 of 8 pts (75%) adjudicated as spleen responders at w72 maintained the response. None of the 8 pts who had not obtained a spleen response at w72 acquired it at the last FU. According to ELN/IWG-MRT criteria of disease response, 7 pts had partial response, 11 had stable disease. At abdominal vessel eco scan, thrombosis improved in 3 of 12 evaluated pts (25%) and remained stable in the remaining 9. Of the 16 pts with endoscopic evaluation at last FU, complete resolution of oesophageal varices was documented in 3/12 with baseline varices (25%), worsening in 4 (33%), stable in 5 (42%), while no de-novo formation of F1 varices was documented in the remaining 4 (33%). No pt had gastrointestinal bleeding episodes. Exploratory endpoints. Included changes in the level of JAK2V617F variant allele burden (VAF) at last FU, available in 13 of 15 JAK2V617F mutated pts. VAF remained stable in 2 pts (13%), increased by 34% (range 25-40) in 3 pts, while 8 pts (62%) had a reduction 〉10% (range 18-96), of whom 6 (46%) had a reduction 〉50% (median 82%, range 70-96). By correlative analysis of JAK2 VAF changes and spleen response, 3 of 6 pts with VAF reduction of 〉50% had complete spleen response, as compared to none of the 3 pts who had an increase of VAF. Conclusions. After a median follow-up of 5.5 years, ruxolitinib continues to be safe in pts with MPN-associated SVT and maintains efficacy against splenomegaly in 33% of the pts. Of note, the large majority of pts (67%) showed stabilization or improvement of oesophageal varices, supporting the hypothesis that sustained reduction of enlarged spleen might contribute to decrease the upstream venous system pressure. Significant reduction of JAK2V617F VAF〉50% was documented in 40% of the pts, although it was not clearly correlated with clinical improvement. Disclosures Rumi: novartis: Honoraria, Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Ruxolitinib use in essential thrombocythemia

Beschreibung: Abstract 314 Background: Akt/mTOR activation has been found in association with dysregulated JAK2/STAT5 signaling due to JAK2V617F mutation. Increased phosphorylation of STAT5 and Akt was detected in patients (pts) with myeloproliferative neoplasms (MPN) (Grimwade LF, BJH 2009). We reported (Bogani C, ASH 2009) that RAD001, an oral inhibitor of mTOR, inhibited the proliferation of human and murine JAK2V617F-mutated cells and impaired colony formation by MPN progenitor cells, suggesting potential clinical activity. Methods: We will report final data from an investigator-initiated, multicenter phase I/II trial with RAD001 in myelofibrosis, primary (PMF) and post-polycythemia vera/essential thrombocythemia (PPV/PET MF). Inclusion criteria were intermediate/high risk score (Lille criteria) or need of treatment because of progressing splenomegaly. Phase I involved a 3+3 pts scheme in 3 sequential cohorts at 5.0, 7.5, and 10 mg daily for 3 mo to establish maximum tolerated dose (MTD). Phase II was a two-stage Simon design involving 16+14 pts at MTD for 4 mo. The protocol was approved by IRBs and pts provided informed consent. The study was supported by Agenzia Italiana per il Farmaco (AIFA) and AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM). Results: Phase I: there was no DLT at 10 mg daily, considered as MTD; there were 2 major (MR), 3 moderate (MO) and 1 minor (MI) and 3 no (NR) responses. In part 1 of Phase II, 〉1/16 pts achieved MR; according to study design, 14 additional pts were enrolled in part 2 (n=30). 20 patients had low and 10 intermediate Lille score; according to IWG-MRT criteria, 5, 10, 8 and 7 were low, int-I, int-II and high risk score, respectively. There were 16 PMF, 8 PPV- and 6 PET-MF. 20 pts were JAK2V617Fpos, 3 were MPLW515pos. Patients evaluable for intention-to-treat (ITT) analysis as of aug 1st were 26; the remaining 4 pts will be updated at meeting. Therapy was discontinued in 5 pts: 1 pt's decision at d60 without evidence of any 〉grade-2 toxicity, 2 at d60 and d90 for physician's decision due to grade-2 toxicity, 1 death due to respiratory failure at d60, 1 at d30 for grade-3 acute renal failure. 21/26 pts (81%) were available for per-protocol analysis. Therapy was generally well tolerated; commonest toxicities were grade-2 mouth ulcers and grade-1/2 hypertrigliceridemia. Hematological toxicities: 3 grade-2 and 4 grade-3 reversible anemia, one grade-2 neuthropenia, one grade-2 and 1 grade-3 reversible thrombocytopenia. A reduction of spleen size consistent with CR, PR or NR was obtained in 8%, 46%, and 46% of the pts, respectively. 11 of 21 pts (52%) had complete resolution of systemic symptoms, and 14 of 19 pts (74%) reported disappearance of pruritus. Two pts achieved PR in anemia with decrease in transfusion requirement 〉50%, while in 3 pts Hb increased of 2g/dL. A CR in platelets was obtained in 3 of 19 pts and CR in leucocytes in 2 of 18 pts with abnormal blood count. Overall, according to ITT analysis: 6 major (23%), 6 moderate (23%), 2 minor (8%) and 12 NR (46%) (EUMNET criteria). According to IWG-MRT criteria, there were 6 (23%) clinical improvement. Per-protocol analysis: 33% major, 19% moderate, 5% minor, 43% NR; 24% clinical improvement. No disease progression. Changes induced by RAD001 in some biological parameters were preliminary evaluated and will be finally updated at meeting. Blood levels of CCDN1 mRNA, a target of mTOR, significantly decreased in responders (MR+MO) versus non-responders (P=0.02). In the 13 JAK2-mutated pts who completed the treatment, the V617F allele burden was 61.6+/−15.8 versus 66.6+/−19.6% at baseline. There was a trend (P=0.07) towards a reduction of granulocyte WT1mRNA copy number in responders versus non-responders. We found no correlation of circulating CD34+ cells or CXCR4 expression with clinical response. A set of 46 inflammatory protein markers and cytokines were quantified before and at d30 of treatment. Some, including IL-10 and MIP-1beta, showed significant decrease while others increased, including Factor VII, IL-8 and MMP-2. Levels of MIP-1 beta were significantly lower in responders (P=0.006). Conclusions: These data indicate that mTOR pathway targeting with RAD001 in MF pts induces an appreciable rate of response in splenomegaly, constitutional symptoms, and pruritus, with low-grade toxicity. However, effects on JAK2V617F mutational load were minimal, and should be better evaluated after longer trial duration. Disclosures: Vannucchi: Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This is an investigator-initiated, non-sponsored, clinical trial with RAD001 in myelofibrosis. Paratore:Novartis: Employment.

Beschreibung: Using records from co-located broad-band and digital strong motion instruments, it is first shown that the displacement waveforms obtained by double integration of the accelerogram need not be free of unrealistic baseline drift to yield reliable spectral ordinates up to at least 10 s. Secondly, to provide objective criteria for selecting reliable digital strong motion records for ground motion predictions at long periods, a set of synthetic accelerograms contaminated by random long period noise has been used and the difference between the original accelerograms and the spurious ones in terms of response spectra has been quantified, by introducing a noise index that can be easily calculated based on the velocity waveform of the record. The results of this study suggest that high-pass filtering the digital acceleration record from a cut-off period selected to suppress baseline drifts on the displacement waveform appears to be in most cases too conservative and unduly depletes reliable information on long period spectral ordinates

Beschreibung: Italian seismological project S5 (Definizione dell'input sismico sulla base degli spostamenti attesi) of the 2006-07 DPC-INGV research programs

Beschreibung: Published

Beschreibung: 697-710

Beschreibung: 4.1. Metodologie sismologiche per l'ingegneria sismica

Beschreibung: JCR Journal

Beschreibung: partially_open