ALBERT

Description: The continuous innovation of satellite payloads is leading to an increasing demand of data-rate for on-board satellite networks. In particular, modern optical detectors generate and need to transfer data at more than 1 Gbps, a speed that cannot be satisfied with standardized technologies such as SpaceWire. To fill this gap, the European Space Agency (ESA) is supporting the development of a new high-speed link standard, SpaceFibre. SpaceFibre provides a data-rate higher than 6.25 Gbps, together with the possibility to use multiple Virtual Channels running over the same physical link, each one configurable with flexible Quality of Service parameters. These features make a SpaceFibre network very appealing but also complex to set up in order to achieve the desired end-to-end requirements. To help this process, a Simulator for HIgh-speed Network (SHINe) based on the open-source toolkit OMNeT++ has been developed and is presented in this paper. It supports the simulation of SpaceFibre and SpaceWire protocols in order to help both the final steps of the standardization process and the system engineers in the setup and test of new networks. SHINe allows to precisely simulate common network metrics, such as latency and bandwidth usage, and it can be connected to real hardware in a Hardware-in-the-Loop configuration.

Description: Abstract 2873 International staging system (ISS) and cytogenetics are the main prognostic factors of Multiple Myeloma (MM) but they reflect biologic characteristics of disease without taking into account individual host features. On the contrary, clinical characteristics of single patient could be substantial as to various points of view. For instance, in elderly MM patients, novel therapies reduction or interruption due to toxicity represent the major cause of unsatisfactory outcome. Therefore, it was empirically suggested different schedule of drugs in these “frail” patients but, how the “frailty” should be assessed in every single patient, is still unsettled. Advanced age, poor performance status (PS) and comorbidities are usually applied to recognize the “frailty” but it is not well known which of them are really prominent and whether these parameters, adjusted for conventional prognostic factors, still affect final outcome. We analyzed a population of symptomatic MM diagnosed from 2007 to 2010 included in the Marche Region MM Registry, to assess the frequency of “frailty” features, such as age, PS, comorbidities, cytopenias, renal insufficiency (RI) and lytic bone lesions, and their role on the overall survival (OS) when adjusted for prognostic factors. Comorbidities were scored according to Charlson Comorbidity Index (CCI) that split patients in 4 categories according to number and type of comorbidity. Patients were treated with transplant or standard therapy according to their eligibility. Overall, 88% of patients were treated with new drug-based therapies and 12% with MP. Median age of the 266 patients analyzed was 73 years (range 38–90). Twenty-four percent of patients had IgA MM, fifty patients (23%) had ISS stage=3 and 29/166 (17.5%) had unfavourable cytogenetics. Regarding “frailty” measures, 38% of patients had 〉 75 years, 39% had PS=2–4, 34% had 1 or more comorbidities. The most frequent comorbidities were hypertension (35%), heart diseases (22%), diabetes (15%), neurological diseases (16%), COBP (8%), secondary malignancies (8%) and chronic renal failure (6%). CCI ≥1 was detected in 51%. Increasing comorbitities number and CCI were associated with increased age although 37% of patients aged less than 65 years had CCI ≥2. Moreover, 35% had at least 2 cytopenias, 76% had bone disease and 14% had RI. Fifty patients (19%) died during follow-up. OS at 3 years was 74%. Univariate analysis performed on the total population determined age 〉 65 years (p=0.065), PS=2–4 (p

Description: Extensive chronic graft-versus-host disease (ecGVHD) is characterized by fibrosis similar to that of patients with systemic sclerosis (scleroderma). Since stimulatory autoantibodies against the platelet-derived growth factor (PDGF) receptor (PDGFR) have been found in patients with scleroderma and are responsible for the activation of skin fibroblasts, we tested the hypothesis that these autoantibodies are also present in patients affected by ecGVHD. Serum from 39 patients subjected to allogeneic stem cell transplantation for hematologic malignancies (22 with ecGVHD and 17 without cGVHD) and 20 healthy controls was assayed for the presence of stimulatory autoantibodies to the PDGFR by incubating purified IgG with mouse-embryo fibroblasts lacking PDGFR α or β chains or with the same cells expressing PDGFR α. Stimulatory antibodies to the PDGFR were found selectively in all patients with ecGVHD but in none of the patients without cGVHD. Higher levels were detected in patients with generalized skin involvement and/or lung fibrosis. Antibodies recognized native PDGFR, induced tyrosine phosphorylation, accumulation of reactive oxygen species (ROS), and stimulated type 1 collagen gene expression through the Ha-Ras-ERK1/2-ROS signaling pathway. The biologic activity of these autoantibodies suggests a role in the development of fibrosis and argues for a common pathogenetic trait in ecGVDH and scleroderma phenotypes.

Description: Abstract 2291 Poster Board II-268 Haploidentical bone marrow transplantation (BMT) is an alternative treatment to patients with high-risk hematologic malignancy lacking a HLA-matched donor and those urgently need transplantation. We used a haploidentical-BMT protocol without ex vivo T cell depleted based on the knowledge that marrow grafts have 10 times fewer lymphocytes compared to peripheral blood stem cell grafts and granulocyte colony-stimulating factor (G-CSF) donor priming reduce the incidence of acute GvHD. Materials and Methods: 40 patients (median age of 32, 12-63) with advanced disease or leukemia with poor prognostic features underwent unmanipulated haplo-BMT: 22 with AML, 9 with ALL, 3 with CML, 3 with Hodgkin lymphoma and 3 with plasmacell leukemia. Status at disease: 22 early (first or second comple! te remission), 18 advanced (progressive or refractory disease). All pairs of donors and recipients were identical for one HLA haplotype and incompatible at 2 or 3 loci.The myeloablative conditioning regimens used were different; antithymocyte globuline, cyclosporine, metotrexate, mycophenolate mofetil and basiliximab were used for GvHD prophylaxis. Donors were primed with filgrastim at 4 micrograms/Kg/d for 7 consecutive days. Bone marrow cells were harvest on the 8 day and were infused unmanipulated. Results: the median dose of total nucleated, CD34+ and CD3+cells was 7×10e8/Kg (1.01-28.7), 2.3×10e6/Kg (1.17-6.0) and 23.3×10e6/Kg (9.7-66.6) respectively. 1 patients had a primary graft failure and 5 patients died early prior to engraftment. In the remaining 34 patients, engraftment was seen with median time to granulocyte and platelet recovery of 22 and 27 days respectively; acute GvHD was grade 0 in 17 patients (50%), grade I in 9 (26%), grade II in 7 (20%) and grade IV in 1 (3%). In 29 evaluable patients, chronic GvHD was limited in 3 (10%) and extensive in 1 (3%). Transplant-related mortality at 6 months for early and advantage stage was 22% and 35% respectively. After a median follow up of 18 (3-42) months, 8 patients relapsed; 11 patients (50%) in the early stage and 4 (22%) in advanced phase are now living in haematological remission. The 1-year Kaplan-Meyer probability of disease-free survival is 45% for all patients. Conclusion: the high engraftment rate, low incidence of grade II-IV acute GvHD and an acceptable TRM suggest that G-CSF-primed marrow grafting along with sequential immunosuppression could provide an excellent alternative for patients who lack matched donors. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points Efficacy of imatinib in steroid-refractory chronic GVHD was prospectively compared across 3 different response systems, with high agreement. Validity of quantitative-based assessment of response with NIH criteria was confirmed by its prognostic impact on long-term survival.

Description: Abstract 2828 Poster Board II-804 Studies including thalidomide showed a rate of severe infection that can be life-threatening complication or compromise compliance to therapy ranging from 6% to 22%. Therefore, antibacterial prophylaxis has become a routine clinical practice despite its role in the new-drugs era has to be defined. We performed a post-hoc analysis of patients treated with thalidomide based combinations within controlled trials in order to assess time, type and outcome of infections. We analysed the main demographic and disease related variables to search for factors affecting onset of infections during induction and build a risk model in order to perform targeted prophylaxis. Two hundred and twenty four patients were eligible for this study. Median age was 70 years (range 31-90 years) and 141 patients (63%) had more than 65 years. Fifty three percent of patients had de novo MM whereas the remaining had received thalidomide as second or subsequent lines of therapy. ISS stage 2-3 and renal impairment were present in 156 (69%) and 38 (17%) of patients, respectively. Induction therapy consisted in the following protocols: ThaDD (160 patients: 71.5%), ThaDD-V (42 patients: 19%), VMPT (9 patients: 4%), TD (8 patients: 3.5%) and VTD (5 patients: 2%). Prophylaxis for infections was administered to 168 patients (75%) and consisted of quinolones (72%) or thrimethoprim-sulphamethoxazole (28%). Eighty six patients (38.5%) developed an infection resulting of grade 3-4 in 39 of them (17.5%) (12% grade 3, 5.5% grade 4). Probability of infection at six months was 39% although that of severe infection was 20% (18% at 4 months and just 2% from 4 to 6 months). Among the 39 patients with severe infection, 23 (59%) developed pneumonia, 9 FUO (23%), 6 bacteremia (1 septic shock) and 1 an orbital abscess. Aetiology of severe infection was recognized in 7 patients (4 Gram-negative bacteria, 1 Gram-positive bacteria, 1 CMV and 1 probable fungal infection). Eighty percent of severe infections occurred during the first 3 courses of induction therapy and only 12% during neutropenia. Fifteen percent of patients undergoing antibiotic prophylaxis developed infection vs 25% of patients who did not (p= 0.084). There were no difference between quinolones and thrimethoprim-sulphamethoxazole prophylaxis regarding incidence of infections. The majority of infections were empirically treated and cured with wide spectrum antibiotic therapy except when a specific aetiology was recognized. Only one patient died because of septic shock during neutropenia and 2 patients withdrawn from protocol because of infection. In univariate analysis monoclonal component 〉 2 g (p=0.021), platelets 〈 130.000/ml (p= 0.005), newly diagnosed MM (p=0.083) and antibiotic prophylaxis (p=0.061) were factors predicting severe infection development whereas age, sex, ECOG performance status, MM type, D-S stage, plasmacell infiltration in bone marrow, haemoglobin concentration, serum b2-microglobulin, serum albumin, ISS, serum C-Reactive Protein, serum creatinine, previous stem cell transplantation were not. Cox regression analysis selected monoclonal component 〉 2 g (p=0.015 HR= 1.8) and platelets 〈 130.000/ml (p=0.003 HR= 2.3) as covariates associated to severe infection. The 25 patients without adverse factors, the 125 with 1 and the 74 with 2 adverse factors had a probability of severe infection equal to 4%, 17% and 32 % (p= 0.023), respectively. This model remains useful apart from prophylaxis since the probability of severe infection in patients with at least 1 risk factors receiving prophylaxis is 17% vs 4% in patients without risk factors. Of note, patients developing severe infection had a significantly higher incidence of deep venous thrombosis (DVT) compared with patients who did not (20.5% vs 9%: p= 0.041). DVT occurred after a median time of 0.9 months (range 0.1-5 months; 75% within 2 months) from infection onset. In conclusion, despite antibiotic prophylaxis, patients receiving thalidomide combination therapy can develop severe infections particularly pneumonia. Wide spectrum antibiotic therapy is effective in the majority of cases since viral or fungal infections are very rare. Patients with large size of disease, represented by high MC and low platelets count, are at higher risk of severe infection that in turn significantly increase the risk of DVT. Therefore, these patients at high-risk should receive more suitable antimicrobial prophylaxis. Disclosures: Off Label Use: Thalidomide, Bortezomib and Doxil.

Description: Abstract 3097 Poster Board III-34 Backgound Adolescent and young (

Description: Chronic Graft versus Host Disease (cGvHD) is still the leading cause of late mortality in transplanted patients. Among the new drugs potentially useful in patients with steroid-refractory cGVHD (SR-cGVHD), the Tyrosine Kinase Inhibitor (TKI) Imatinib emerged as promising agent; however in our previous experiences, patient's frailty and their reduced haematological tolerance heavily limited the daily dose of Imatinib (median dose administered was 200 mg/day). Thus we planned to evaluate in the same setting a the safety and activity of a second generation TKI, such as Nilotinib (NIL), characterized by a better haematological tolerance and that could allow to treat SR-cGVHD patients with a higher relative dosage than Imatinib, thus achieving a better efficacy. Basing on this rational we designed a phase I-II study, aimed to individuate the maximum tolerated dose ( MTD) and the activity of NIL in patients with SR-cGVHD (ClinicalTrials.gov ID: NCT01810718). Primary endpoint of the phase I study was to define the dose limiting toxicity (DLT) of NIL, defined as the occurrence of any grade≥3 toxicity during at least one month of treatment. According to the Fibonacci standard 3+3 design, we started from an initial dose of 200 mg/day of NIL, up to a maximum of 600 mg/day. The drug has been supplied free of charge by Novartis Italia, Milan. In the phase II the MTD will be used to define the efficacy of NIL in SR-cGVHD patients, with similar characteristics of the previously Imatinib-treated population. Moreover all the patients enrolled in the phase I were allowed to continue NIL at the same dose, up to a cGVHD progression, if an objective improvement (OI) was documented after 3 months of treatment. We report here the preliminary results of a pre-planned interim analysis, during the phase I study, in 12 patients with SR-cGVHD who received NIL at low dose. The main characteristics of the enrolled patients are reported in table 1. Six patients received NIL 200mg/day and 6 NIL 300 mg/day. Two patients stopped NIL within 30 days: one due to cGVHD progression, the other had asymptomatic hypertransaminasemia (〉5xULN) which normalized 1 month after stopping NIL; these patients received an alternative treatment. In 3 cases severe adverse events (SAE) have been reported: 1 patient had extramedullary relapse of Acute Leukemia 8 months after start of NIL, while 2 patients have been hospitalized; one due to a transient cGVHD flare, without drug interruption, the second for a late cGVHD progression; he eventually died. The most frequent extrahematological toxicities (grade 1-2 according to CTCAE) were headache, nausea, pruritus, cramps, asthenia, constipation, while the main hematological abnormalities were represented by anemia grade 1 (5/12patients), neutropenia gr.1 (1/12 patients) and lymphocyte count increase gr.2 (1/12 patients). (tab.2) With a median F-U of 10 months (range 4-20), 10 patients are alive, while two died for cGVHD progression (7 and 9 months after the enrollment). After 3 months of treatment with NIL 6 patients (50%) achieved an OI and 4 (33%) a stable disease; all the 10 patients continued Nilotinib at the same dose until ≥6 months of treatment: after 6 months we observed 5 OI, 1 stable disease and 2 mixed responses (2 lung responses with skin failure), while in 2 the response evaluation is still ongoing. These preliminary data suggest that, like Imatinib, NIL at low doses is safe and effective in SR-cGVHD patients; up to day the MTD has not been still achieved, therefore only after the end of the phase I study we will be able to fully define the NIL activity. This study is supported by GITMO (Gruppo Italiano Trapianto di Midollo Osseo). Disclosures: Off Label Use: Bendamustine.

Description: ThaDD regimen has provided significant results in recurrent/relapsed multiple myeloma (MM) patients (Offidani et al, 2006). In order to further improve those results without significantly increasing toxicity, we decided to include Velcade, synergic as per activity but not toxicity with the other drugs of ThaDD regimen. ThaDD-V was scheduled as follows: Thalidomide 100 mg/day, pegylated liposomal Doxorubicin 30 mg/sm iv days 4; Dexamethasone 20 mg days 1–2, 4–5, 8–9, 11–12 and Velcade 1.3 mg/sm iv days 1, 4, 8, 11 every 28 days (induction therapy). Patients received bortezomib for alternate cycles as following: 1 mg/sm day 1, 8, 15 and dexamethasone 20 mg days 1–2, 8–9, 15–16 and thalidomide 100 mg/day and dexamethasone 40 mg/day for 4 days monthly for a total of six cycles as consolidation therapy. Then patients received thalidomide 100 mg/day until relapse (maintenance therapy). Actually 20 patients (7 M, 13 F; median age 62.5 yrs, range 31–75) are assessable for response and toxicity. Five pts (25%) showed WHO performance status (PS) 〉 1, 9 pts (45%) presented refractory disease, 8 pts (40%) were priorily administered ≥ 2 lines of a treatment and 14 patients (70%) were submitted to one previous autologous stem cell procedure. Seven patients (35%) had extramedullary disease and 7 had unfavourable cytogenetics. Twelve patients scored an ISS ≥ 2 and 11 (55%) were in first remission for ≤ 12 months median duration. No patients were previously treated with Velcade, whereas six patients had received short-term Thalidomide treatment. Response was assessed according to IMVG uniform response criteria. Seventeen of 20 patients responded after at least one chemotherapy cycle reporting 5 (25%) sCR, 3 CR (15%), 8 VGPR (40%) and 1 stable disease. Three patients (15%) had extramedullary progressive disease. In a median follow-up of 12 months, 2 (10%) patients progressed and 1 (5%) died from cardiac infarction. Time to progression and overall survival were 73% and 95% at 12 months. We observed 4 grade 3 thrombocytopenia, 2 grade 3 DVT, 1 grade 3 diarrhoea, 1 grade 3 asthenia, 1 grade 4 infection and 1 grade 3 dermatological toxicity. Six patients developed grade 2 peripheral neuropathy and other three grade 3. In conclusion, ThaDD-V is extremely active in advanced MM patients as demonstrated by the elevated precentage of high quality remission. Nevertheless, patients are at substantial risk of developing neurotoxicity so the protocol was amended as per Velcade dose intensity and Thalidomide dose.

Description: The oral anticoagulant therapy (OAT) in oncologic patient is often problematic because both the haemorragic risk and the thrombotic risk, i.e. the recurrence of venous thromboembolism, are increased. Many studies have been conducted in patient with solid neoplasms; it remains still unclear whether these results could be entirely extrapolated to patients with haematological malignancies. Our aim was to analyse the clinical outcomes and the control of anticoagulation, measured as % time in target INR range, in the patients with cancer compared to patients without cancer; moreover we focused on patients with haematological neoplasms. A total of 500 patients were recruited in 6 years, regardless of the indication for OAT; 146 (29%) of them were affected by cancer (47 haematological and 99 solid neoplasms); those being treated with warfarin for less than 1 month were excluded from this analysis. It resulted that patients affected with cancer had a worse anticoagulation control, compared to those without cancer (55% vs 60%; p