ALBERT

Description: Abstract 964 Background: High dose immunosuppressive therapy and hematopoietic stem cell transplantation (HSCT) has shown efficacy in severe or rapidly progressive systemic sclerosis (SSc) in phase 1 and 2 trials with durable responses in two thirds of patients (pts), while a recent phase 2 randomised trial in 19 SSc pts showed superior benefit of HSCT over iv pulse cyclophosphamide (Cy) on skin score and lung function. Methods: The ASTIS-trial (Autologous Stem cell Transplantation International Scleroderma trial) is a multinational prospective randomized controlled phase 3 trial, comparing safety and efficacy of HSCT versus Cy in early progressive dcSSc pts with disease duration of a) 4 years or less and evidence of organ involvement or b) of 2 years or less and evidence of systemic inflammation with or without major organ involvement. Major exclusion criteria were: concomitant severe SSc disease (mean PAP 〉 50 mmHg, DLCO 〈 40% predicted, creatinine clearance (CCl) 3months oral) treatment), liver failure. Pts randomized to the transplant arm underwent mobilization with Cy 2×2 g/m2 + G-CSF 10mcg/kg/d, conditioning with Cy 200 mg/kg, rbATG 7.5 mg/kg, followed by reinfusion of CD34+ autologous HSCT. Controls were treated with 12× monthly iv pulse Cy 750 mg/m2. Crossing over was allowed after 2 years. The primary endpoint was event-free survival (EFS), defined as survival until death or development of major organ failure at 2 yrs. Toxicity according to WHO criteria and progression free survival (defined as worsening of modified Rodnan skin score, functional ability, major organ function) were the main secondary endpoints. The effects of treatment were analyzed on an ITT basis and by comparing EFS using the KM survival curves (using log-rank test) and Cox models. Results: 156 pts (female 59%), from 27 centers were enrolled in 10 countries from March 2001 until October 2009 and randomized to HSCT (n=79) or iv pulse Cy (n=77). Seventy-five pts in each arm started treatment, 70 pts in HSCT and 58 pts in control groups completed treatment. The median time (Interquartile Range (IR)) from randomization to completion of treatment was 93 (43.0) days in the HSCT and 338 (41.75) days in the control groups respectively. Baseline characteristics (mean (SD)) of the pts were: age 44 (11.2) yrs, SSc duration 1.4 (1.3) yrs, BMI 24 (14.4), Rodnan skin score 25 (8), HAQ 1.35 (0.8), prior Cy therapy 22%, creat cl 116 (39.5) ml/min, LVEF 65% (8.5), DLCO 59% (14), with no significant differences between the 2 arms. With data cut at 1 May 2012, median follow-up (IR) are 33 (42.0) and 27 (34.0) months in the HSCT and control groups respectively. Forty two events occurred : 18 in the HSCT group (16 deaths and 2 irreversible renal failures) and 24 in the control group (24 deaths). Event-free survival was time-dependent with a hazard ratio at 84 months of 0.22 (95% CI 0.08–0.58, P= 0.002). Eight deaths (including 1 during mobilization and 1 after conditioning) in the HSCT group were deemed treatment-related by the independent data monitoring committee with heart failure (3), ARDS (2), multiple organ failure (2) and pulmonary oedema (1) as the causes of death. In the control group, none died from treatment causes and most deaths were due to progressive disease. Eight pts in the control arm received rescue HSCT treatment, one of whom later died from secondary acute myeloid leukaemia. Two HSCT pts received rescue iv Cy therapy. Conclusions: The ASTIS-trial is the first international, investigator-initiated, phase 3 HSCT trial in early diffuse cutaneous systemic sclerosis. The data show that despite 10% treatment-related mortality, long term event-free survival and overall survival were better in the HSCT group than in the group treated with iv pulse cyclophosphamide. (Funded by the European Group for Blood and Marrow Transplantation, European League Against Rheumatism, AP-HP, NIHR, DIGR, Imtix-Sangstat, Miltenyi-Biotec, Amgen Europe; Current Controlled Trials number, ISRCTN 54371254). Disclosures: No relevant conflicts of interest to declare.

Description: Key Points Symptomatic extensions, whether or not reaching the SFJ, are common complications of SVT. Their frequency and associated risk of venous thromboembolic complications and medical resource consumption are reduced by fondaparinux.

Description: Venous thromboembolism (VTE) is a major therapeutic issue in cancer. Advances in this field and heterogeneities in clinical practices prompted us to establish guidelines related to VTE treatment and to central venous catheter thrombosis (CVCT) management. in cancer patients according to the SOR Standards, Options: Recommendations (SOR) methodology for the development of evidence-based Clinical Practice Guidelines (CPG) as endorsed by the French National Cancer Institute. Methods: After reviewing the published studies on the topics between 1999 and 2007, a first version of the guidelines was based on the levels of evidence derived from analysis of the 38 out of 418 selected studies for VTE treatment and the 40 out of 175 selected studies for the CVCT management. The recommendations were classified as Standards or Options and then peer-reviewed by 65 independent experts. Detailed methodology is available at www.sor-cancer.fr Standards in cancer patients: The treatment of VTE should be based on Low Molecular Weight Heparins (LMWH) at curative doses for at least 3 months. During the initial treatment (up to 10 days), there are no specific requirements and all drugs approved (including LMWH, Unfractionnated Heparin (UFH), fondaparinux and danaparoid) may be used. Beyond the first 10 days, VTE treatment should be based on LMWH at curative doses for at least 3 and optimally for 6 months, as validated with the following drugs and dosage regimens: dalteparin 200 IU/kg once daily for one month, then 150 IU/kg once daily; enoxaparin 150 IU/kg once daily; and tinzaparin 175 IU/kg once daily. In case of: severe renal impairment, UFH should be used rapidly followed by Vitamins K Antaogonist (VKA) for at least 3 months; severe Pulmonary Embolism (hemodynamic failure), the indications and usages of thrombolytic drugs are the same as in non-cancer patients; absolute contra-indication to anticoagulation or VTE recurrence despite optimal anticoagulation, vena cava filters (VCF) should be considered; intracranial malignancies, VTE treatment is the same as in cancer patients with non-intracranial tumors. CVCT treatment relies on long term use of LMWH. In case of severe renal failure, UFH with early AVK must be used. Treatment is to be continued as long as the catheter is maintained. This can only be achieved if the catheter is functional, well positioned, not infected and if adapted anticoagulation has resumed the CVCT. If catheter withdrawal is necessary, there is no standard concerning the anticoagulation management. CVCT prophylaxis relies on positioning the catheter distal extremity at the “superior vena cava - right atrium” junction. Systematic CVCT anticoagulant prophylaxis is not recommended. Options: Treatment of VTE: If LMWH administration for 3 months is impossible, short-term use of LWMH followed by VKA for at least 3 months may be proposed. It is recommended to administer LMWH for 3 to 6 months; LMWH should be used according to the same curative dosage regimen as during the first 3 months. Beyond the first 6 months, the anticoagulant treatment should be continued as long as the cancer is active or treated. In the event of a first VTE episode secondary to a transient risk factor and if the cancer is not active nor treated, anticoagulation may be discontinued after 6 months. The choice between LMWH and VKA depends on their benefit-risk ratio (influenced by drug interactions, chemotherapy, invasive procedures, and general health status) and acceptability. If a VCF is considered, a retrievable VCF may be discussed. CVCT treatment: If another catheter has to be inserted, prior evaluation of the venous circulation by scanner or ultrasound examination is recommended. If prolonged use of LMWH is impossible, VKA can be proposed. In case of severe superior vena cava syndrome, fibrinolytics can be used in the absence of contra-indications. Treatment by LMWH can be stopped 6 weeks after catheter withdrawal in non active cancer or after 3 to 6 months of LMWH followed by VKA in the other cases. CVCT prophylaxis: Right side catheter insertion and vein localisation by ultrasonography are preferred. Conclusion: The French recommendations further support the 2006 Italian and the 2007 North American guidelines on VTE treatment in cancer patients and were extended to the use of VCF and treatment of patients with intracranial malignancies. In addition, we provide recommendations on CVCT treatment in cancer patients.

Description: Background: Isolated superficial vein thrombosis (iSVT) (i.e. without concurrent deep-vein thrombosis or pulmonary embolism) is a frequent event. Its clinical significance and management are controversial. Data on long-term follow-up are scarce and the impact of anatomical characteristics of iSVT on the risk of venous thromboembolism (VTE) (DVT and/or PE) recurrence has not been assessed. Objective: To determine the impact of anatomical characteristics of iSVT on the long-term risk of VTE recurrence. Methods: Using data from the The OPTIMEV (OPTimisation de l'Interrogatoire dans l'_evaluation du risque throMbo-Embolique Veineux) study, a prospective, observational, multicenter study, we assessed at 3 years in patients recruited for an objectively confirmed iSVT i) cumulative rates of DVT, PE and SVT recurrences using the Kaplan-Meier method; and ii) anatomical predictors of VTE recurrence (SVT involving the sapheno-femoral junction (i.e. ≤3 cm), SVT of the trunk of the great saphenous vein, bilateral SVT, SVT occurring in a varicose vein (i.e. C≥2 according to CEAP classification) using a Cox multivariable model adjusted for age, sex, cancer and personal history of VTE. At baseline, all patients with SVT underwent a complete bilateral swhole leg ultrasound to exclude concurrent DVT and during follow-up, all suspected VTE recurrences were confirmed/ruled out with objective tests. All recurrences were centrally adjudicated by the study's expert committee. Results: Among the 479 recruited patients with iSVT, 12.5% (n=60) had a thrombotic recurrence during the 3 years of follow-up. Cumulative rates of recurrence as a PE, DVT and iSVT were 1.9%, 4.8% and 5.8%, respectively. In multivariate analysis, a thrombus involving the sapheno-femoral junction at baseline independently increased the risk of VTE recurrence (HR=3.34 [1.5-7.2]). Presence of varicose veins also increased the risk but this result did not reach statistical significance (HR=1.8 [0.9 - 3.9], p=0.11). Conclusion: In an unselected population of patients with iSVT, long-term risk of VTE recurrence is substantial. Involvement of the sapheno-femoral junction is a strong independent predictor of VTE during the subsequent 3 years. Our results suggest the need for more aggressive management and follow-up of patients with iSVT exhibiting this anatomical characteristic. Disclosures Galanaud: Daichi: Membership on an entity's Board of Directors or advisory committees, Research Funding; bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sevestre:bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daichi: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pernod:pfizer: Consultancy; leo: Consultancy; bristol meyers: Consultancy; Daichi: Consultancy; bayer: Consultancy. Brisot:bayer: Membership on an entity's Board of Directors or advisory committees; daichi: Membership on an entity's Board of Directors or advisory committees. Quéré:3-M: Research Funding; thuasne: Research Funding; aspen: Research Funding; daichi: Membership on an entity's Board of Directors or advisory committees; bayer: Membership on an entity's Board of Directors or advisory committees; leo: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 630 Background: Cancer constitutes a strong risk factor for proximal deep-vein thrombosis (DVT). After a proximal DVT, the risk of being diagnosed a previously undiagnosed cancer in the following years is high. This has justified a cancer screening in this situation, the optimal modalities of which (extensive vs. limited screening) are currently under evaluation. However, little is known on the risk of subsequent cancer in case of symptomatic isolated distal DVT (e.g. infra-popliteal DVT without PE) and symptomatic isolated superficial vein thrombosis (SVT) (e.g. without concomitant DVT and PE). The value of cancer screening is therefore debated in these situations. Yet, each of those two other clinical expressions of venous thromboembolic disease (VTE) in the lower limbs is at least as frequent as proximal DVT. Objective: As compared with patients with a first episode of symptomatic isolated proximal DVT (e.g. without PE), we aim assessing the risk of subsequent cancer in patients with a first isolated distal DVT or with a first isolated SVT. A secondary objective was to assess the influence of anatomical characteristics of distal DVT and SVT (deep calf DVT vs. muscular DVT and SVT on varicose vein vs. SVT on non-varicose vein) on the risk of subsequent cancer. Methods: We analysed the data from the OPTIMEV prospective, observational, multicenter study of consecutive in and outpatients recruited after an objectively confirmed symptomatic VTE and followed up three years. All VTE events were diagnosed via a standardized bilateral whole leg compression ultrasonographic protocol screening the entire deep and superficial venous networks. Results: 327 patients with a proximal DVT, 536 with a distal DVT, and 329 with an SVT fulfilled our study's inclusion criteria. 2.9% (n=35) of patients were lost to follow-up before 3 years. At 3 years cumulative rates of cancer were similar whatever the kind of VTE considered (Figure 1). Incidence of subsequent cancer was respectively of 3.9% [2.2 – 6.1] in case of proximal DVT, 4.1% (95% CI [2.7 – 6.1]) in case of distal DVT and 3.1% [1.7 – 5.7] in case of isolated SVT. Neither anatomical characteristics of distal DVT (cumulative rates of subsequent cancer 4.2% [2.3 – 7.4] in case of muscular DVT, 3.7% [1.6 – 8.6] in case of deep calf DVT and 4.3% [1.8 – 9.9] in case of combined muscular and deep calf DVT, p=0.98) nor anatomical characteristics of SVT (cumulative rates of subsequent cancer 1.9% [0.5 – 7.2] in case of SVT on non-varicose vein and 3.4% [1.9 – 7.4] in case of SVT on varicose vein, p=0.4) significantly influenced the risk of subsequent cancer. Main strengths/limitations: This is the largest prospective observational cohort of in and out patients with an objectively confirmed isolated SVT or isolated distal DVT, managed in routine practice, and with a long-term follow-up. Our results only apply to first episodes of isolated SVT or distal DVT. As compared with previous reports on the risk of subsequent cancer in case of VTE, our population of DVT/SVT patients was at low risk of cancer a priori. Indeed, we only included first episodes of VTE, most of which were diagnosed and managed in an outpatient setting and/or were associated with a transient risk factor. Therefore the number of newly diagnosed cancer was limited and we may have lacked statistical power for some sub-group analyses. However our rate of subsequent cancer in proximal DVT patients was in the range of that from recent studies and significantly higher than the expected rate of cancer in the French general population of the same age. Conclusion: In patients managed in routine practice without previous history of cancer or VTE, every clinical expression of lower limb VTE (proximal DVT, distal DVT and SVT) is associated with a similar risk of subsequent cancer. Anatomical characteristics of distal DVT and SVT do not seem to have a strong impact on this risk. These results suggest that cancer screening should not be modulated according to the deep-proximal, deep-distal or superficial location of lower limb thrombosis. Cumulative rates of subsequent cancer according to the proximal, distal or superficial location of VTE were estimated with the Kaplan-Meier method and compared with logrank test. Disclosures: No relevant conflicts of interest to declare.