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2016 Annual Minutes 0 M. Carrier Haemotasis &Malignancy SSC Committee meeting Minutes – Montpellier 2016 Chair: Marc Carrier (present) Co-Chairs: Guy Meyer (present); Simon Noble (regrets); Alok Khorana (regrets); Cihan Ay (regrets); Nigel Mackman (regrets); Joseph Palumbo (regrets). 1)      Prediction and prevention of cancer-associated thrombosis a.       Biomarkers for the prediction of VTE in Cancer Patients – A Falanga, Italy  i.      Review of the evidence on the different biomarkers and the risk of cancer-associated thrombosis (CAT) ii.      Report of the preliminary results of the second cohort (metastatic cancer patients)  of the Hypercan study b.      Primary prevention of VTE in cancer patients – G Myer, France i.      Excellent review of the different primary prevention trial in ambulatory cancer patients receiving chemotherapy. 2)      Clinical debate: Pro and con occult cancer screening in patients with unprovoked VTE – M Carrier & G Le Gal. a.       Review of the recently published literature on the efficacy of occult cancer screening b.      ACTION: i.      Proposal for Guidance statement on occult cancer screening in patients with unprovoked VTE ii.      Interested SSC members: A Delluc (France)and Ramon Lecumberri (Spain) 1.       M Carrier to follow-up with interested members 2.       Send a Proposal to SSC Chair by fall 2016 3)      Recurrent VTE and cancer-associated thrombosis a.       NETS in cancer-associated coagulopathy – J Thaler, Austria i.      Review of the new potential importance of NETS in cancer patients b.      Risk factors for recurrent CAT- A Delluc, France i.      Excellent review of the risk of recurrent VTE in CAT patients 4)      Tools for clinical research and updates of SSC initiatives a.       Statistics for Thrombo-Oncologists i.      Updates on new statistical (methods) requirements for cancer research (competitive risk, complex risk factors, etc.) b.      Updates: i.      Coagulopathy in Prostate Cancer Patients Under Androgen Deprivation 1.       ACTION: a.       Proposal for a cohort study assessing TEG in cancer patients                                                                                                                   i.      M Carrier to assess potential resources available at SSC meeting on May 27th                                                     ii.      SSC registry on incidental PE in cancer patients 1.       M Di Nisio has enrolled 461 patients (total sample 600). Should be done within next year. 2.       ACTION: a.       Final results to be presented in Berlin 2017                                                    iii.      Other SSC Projects: 1.       S. Noble a.       Qualitative analyses of VTE in cancer position statement 2.       J. Palumbo a.       Pediatrics’ VTE cancer guidelines collaboration with the Pediatric SSC group 3.       C. Ay a.       Use of D dimer in cancer-associated VTE 4.       ACTION: a.       Aim to complete on-going projects by SSC 2017                                                            iv.      New SSC project proposal: 1.       H Rasmussen a.       Active cancer definition in clinical trials 2.       S Noble a.       Anticoagulation in patients with cancer undergoing chemotherapy treatment 3.       ACTION: a.       Identify members willing to participate on the projects b.      Submit proposal to SSC Chair by fall 2017 
by M. Carrier
Wednesday, June 8, 2016
2015 Annual Minutes 0 L. Schmeidler Chairman: Alok A. Khorana Co-Chairs: Marc Carrier, Howard A. Liebman, Nigel Mackman, Simon Noble, Ingrid Pabinger, Joseph S. Palumbo  Education Session The education session was chaired by Dr.s Khorana and Carrier and included Dr.s Carrier and Noble as speakers.  Dr. Carrier spoke about occult malignancy screening after unprovoked VTE, particularly in light of two trials to be presented at ISTH 2015. Although results of these studies were not yet available, Dr Carrier identified study design and expectations for outcomes. He proposed a guidance statement from SSC of ISTH after results of these studies are known to better inform hematologists on practice issues. Dr. Noble provided an overview of qualitative research in hematology, how it differs from generally accepted standards and sample sizes in quantitative research and how it can inform patient care.  SSC Working Session The session was first chaired by Dr.s Mackman and Pabinger. The second half was chaired by Dr.s Ay and Zwicker. Dr.s Palumbo, Mackman and Pabinger described recent results linking platelet activation with hemostatic factors and tumor biology. Dr. Mackman posed the question of how therapeutic targeting of platelets could affect malignancy outcomes and potentially even prevent thrombosis in this setting. Dr. Khorana reviewed recent data regarding clinical predictors and biomarkers of recurrent VTE in malignancy, in context of the recent completed CATCH study. Dr. Falanga described early findings and study design of an Italian study of biomarker screening for cancer-associated thrombosis, the HYPERCAN study. Dr. O’Connell described emerging data regarding prevalence and outcomes related to incidental thrombosis in malignancy. She was followed by Dr. Di Nisio who presented the new ISTH guidance statement on incidental thromboembolism in malignancy, recently published in JTH. Dr. Ay described how network analysis could evaluate anticoagulants in different clinical trials indirectly. Dr. Othman presented data suggesting a strong hypercoagulable state in prostate cancer. Dr. Zwicker presented data on intracranial bleeding in patients with brain metastases and a guidance proposal to better categorize such bleeds in future studies. Dr. Palumbo described draft guidance statement proposal encompassing venous thromboembolism in pediatric cancer patients. Finally, Dr Kamphuisen provided an update on the LONGHEVA trial which has now transformed into an online registry and asked for SSC members to participate. The session was adjourned at 6.40 PM.
by L. Schmeidler
Sunday, June 21, 2015
2014 Annual Minutes 0 A. Khorana Hemostasis and Malignancy Chairman: Alok A. Khorana (USA) Co-Chairmen: Marc Carrier (Canada), Howard Liebman (USA), Nigel Mackman (USA), Ingrid Pabinger (Austria), Joseph Palumbo (USA), Jeffrey Zwicker (USA) Tuesday, 24 June (14:00-18:00)  Attendance: Alok A. Khorana (USA), Marc Carrier (Canada), Howard Liebman (USA), Nigel Mackman (USA), Ingrid Pabinger (Austria), Joseph Palumbo (USA) and Jeffrey Zwicker (USA)   Invited Speakers: Bo Zhang (abstract), Jeffrey Zwicker, Alok A. Khorana, Howard Liebman, Marc Carrier, Ingrid Pabinger, Nigel Mackman, Brian Cooley, Marcello Di Nisio  There were 10 presentations, including guidance documents, updating subcommittee activity and discussing new proposals.    The first portion of this SSC session, co-chaired by Drs Pabinger and Khorana, focused on activity by the Subcommittee in generating new data and developing guidance statements. Dr. Zwicker provided an update of recently published data regarding thromboprophylaxis in hospitalized cancer patients. Dr. Khorana discussed a draft guidance statement on prevention of VTE in medical cancer outpatients. Dr. Liebman discussed potential roles for direct oral anticoagulants in prevention of cancer-associated thrombosis and Dr. Carrier discussed their role in treatment.   The second portion of this SSC session, co-chaired by Drs Palumbo and Mackman, provided updates of SSC activity on clinical and translational projects.  Dr. Pabinger provided new information from the ongoing Vienna CATS registry, regarding the role of interleukins. Dr. Mackman proposed a TF standardization project and invited collaborators. Dr. Cooley discussed mouse models of cancer-associated thrombosis. Finally, multiple investigators provided brief updates on the larger ongoing clinical trials in the field of cancer-associated VTE including the CATCH trial of treatment of VTE with tinzaparin (Khorana), the PHACS trial evaluating the use of dalteparin as prophylaxis in cancer outpatients at high risk for VTE (Khorana), the SOME and PERIOP trials (Carrier), long-term treatment of VTE after 6 months the LONGHEVA trial now converted to a registry (Kamphuisen), Dr. DiNisio presented data from a registry of incidental VTE. In this multicenter, prospective study, patients with unsuspected pulmonary embolism are followed up for to one year to assess the incidence of recurrent symptomatic VTE, bleeding, and mortality. The status of the study was presented with an update of the number of centers involved and patients included.  The meeting was adjourned at 18:00. 
by A. Khorana
Thursday, June 19, 2014
2013 Annual Minutes 0 A. Khorana Hemostasis & MalignancyJune 29, 201314:00-18:00, Mondriaan IV Chairman: Alok A. Khorana (USA) Co-Chairs: Marc Carrier (Canada), Agnes Y. Lee (Canada), Howard A. Liebman (USA), Marina Marchetti (Italy), Ingrid Pabinger(Austria), Joseph S. Palumbo (USA), Wolfram Ruf (USA), Jeffrey Zwicker (USA) Additional Invited Speakers: Chris Holmes, Thomas Ortel, Cihan Ay, Henri Versteeg, P. W. Kamphuisen, M. Di Nisio, Guy Meyer There were 12 presentations, including 3 educational talks, updating subcommittee activity and discussing new proposals. The 3 educational talks comprised the first session. Dr. Lee reviewed state-of-the-art treatment of cancer-associated thrombosis, given the arrival of novel oral anticoagulants (NOACs) as an option. She provided a summary of the evidence base (or lack thereof) supporting the use of low-molecular-weight heparins, warfarin and NOACs in this setting. Dr. Holmes provided a comprehensive overview of anti-platelet therapy and its role in the setting of malignancy, given multiple recent epidemiologic and trials data suggesting benefit in terms of patient outcomes in this setting. Dr. Ortel (who spoke later in session owing to late arrival) reviewed incidence and prevalence of bleeding complications in malignancy, both in the presence and absence of anticoagulation. The first SSC non-educational session focused on activity by the Subcommittee in developing guidance statements. Dr. Carrier provided an update on a recently developed guidance statement evaluating the appropriate treatment of recurrent VTE in the setting of malignancy, keeping in mind bleeding concerns. This paper was recently accepted for publication by JTH. Dr. Zwicker provided an overview of a guidance statement on the treatment of catheter-associated thrombosis. Dr. Khorana discussed emerging and recent data on outpatient thromboprophylaxis in malignancy including results of SAVE ONCO, PROTECHT and Microtec; validation of a risk score; and recently published subgroup analyses of SAVE ONCO and PROTECHT utilizing the risk score. A summary of these data has led to the development of new guidance from the SSC on outpatient thromboprophylaxis in cancer patients and a draft version of these statements was reviewed as well. Dr. Lee provided an update on the SSC work on developing a guidance statement on incidental VTE including aspects related to diagnosis and management in an era where a high proportion of VTE are diagnosed incidentally. The second SSC session provided updates of SSC activity on clinical and translational projects. Dr. Palumbo was scheduled to speak in this session but spoke earlier in lieu of Dr. Ortel and provided a comprehensive overview of the literature around the role of hemostatic factors in malignancy including their role in non-hemostatic processes such as angiogenesis. Dr. Pabinger provided an update on results from their registry which will soon be celebrating its 10th anniversary. This registry, the Vienna Cancer and Thrombosis Study (CATS) is an ongoing prospective non-interventional study for definition of risk factors for venous thromboembolism. Recently novel clinical risk factors were identified, including high-grade histological phenotype and regional (lymph node positive) stage. In addition the group has found that presence of varicose veins increases the risk of cancer-associated VTE. Dr. Carrier provided an update of a pooled analysis of cancer patients from clinical trials of prophylaxis in acutely ill medical inpatients. Unfortunately, the results of this analysis do not confirm a clear benefit to cancer patients from prophylaxis, likely due to under-powering of sample size. Clearly, more data are necessary in this regard and Dr Carrier outlined potential proposals. Dr. Versteeg outlined a call for new translational studies in the setting of malignancy and VTE, focusing on tumoral coagulation factors, and immunohistochemistry. Finally, multiple investigators provided brief updates on the larger ongoing clinical trials in the field of cancer-associated VTE including the CATCH trial of treatment of VTE with tinzaparin (Lee), the PHACS trial evaluating the use of dalteparin as prophylaxis in cancer outpatients at high risk for VTE (Khorana), the SOME and PERIOP trials (Carrier), long-term treatment of VTE after 6 months the LONGHEVA trial (Kamphuisen), Dr. DiNisio presented enrollment data from a registry of incidental VTE. In this multicenter, prospective study, patients with unsuspected pulmonary embolism are followed up for to one year to assess the incidence of recurrent symptomatic VTE, bleeding, and mortality. The status of the study was presented with an update of the number of centers involved and patients included Dr. Zwicker presented study design of a new proposed trial of prophylaxis (CAT IQ). The session chairs thanked the audience for their participation. The meeting was adjourned at 18:00.   
by A. Khorana
Wednesday, June 19, 2013
2012 Annual Minutes Locked Topic 0 A. Lee Hemostasis and Malignancy Subcommittee Minutes 30 June 2012 Chairman: Agnes YY Lee (CA) Co-chairmen: Marc Carrier (Canada), Dominique Farge (France), Alok Khorana (USA), Howard Liebman (USA), Marina Marchetti (Italy), Ingrid Pabinger (Austria), Wolfram Ruf (USA), Jeffrey Zwicker (USA) Attendance: Wolfram Ruf (US), Dominique Farge (FR), Marina Marchetti (IT), Jeff Zwicker (US), Marc Carrier (CA), Ingrid Pabinger (AU), Howard Liebman (US) Invited Speakers: Carla Vossen (NL), Cihan Ay (AU), Marcella DiNisio (IT), Sam Schulman, Pieter Kamphuisen  There were 11 presentations updating subcommittee activity and discussing new proposals.They were divided into 2 sessions: 1) Update on Current Projects and Clinical Trials and 2) New Proposals and Hypotheses.  Update on Current Projects and Clinical Trials Standardization of tissue factor assays Marina Marchetti (IT)  Dr. Marchetti provided an update of the tissue factor (TF) standardization project.Lyophilized cell lysates from MDA.MB.231 breast cancer cell line have been prepared in Dr. Anna Falanga’s laboratory in Bergamo, Italy to be used as a possible TF reference material. A proposal was made to distribute and test this material amongst various laboratories involved in the TF Working Party.The proposal was accepted and the subcommittee will apply for funding from SSC to cover logistic costs.  Defining VTE in Oncology Trials Marc Carrier (CA)  Dr. Carrier presented the rationale and development of the subcommittee’s recommendations on standardized the definition, analysis and reporting of VTE in oncology studies.As noted previously, the lack of standardization and the use of National Cancer Institute’s Common Toxicity Criteria to classify adverse events undermine the accuracy and transparency of VTE reporting.Furthermore, competitive risk analysis is a more appropriate method to account for the high incidence of death in this patient population.A position paper has been prepared and circulated to co-chairs prior to this meeting.Once approval has been received by the subcommittee co-chairs, the position paper will be submitted to JTH for publication.  International guidelines for antithrombotics in cancer patients Dominique Farge (FR)  D Farge-Bancel presented the final draft of the International Good Clinical Practices Guidelines for Antithrombotic in Cancer Patients. Co-authors of the document include the following collaborators: P Debourdeau (co-first author), M Beckers, C Baglin, R Bauersachs, B Brenner , D Brilhante, A Falanga, G Gerotzafias, A Kakkar, A Khorana, R Lecumberri, A Lee,M Mandala, M Marty, M Monréal, S Mousa, N Haim , S Noble, I Pabinger, P Prandoni, M Prins, M Qari, M Streiff, H Bounameaux, and H Buller.The project was initiated by the "Groupe Francophone Thrombose et Cancer” and the Academic Medical Centre (AMC), Amsterdam. The guidelines were prepared according to the GRADE methodology based on a literature review of the studies published between 1996 and 2011.Methodological support and quality control were provided by the French national cancer institute (INCa).There wasn’t time to discuss these guidelines.  2012 ACCP Guidelines on Cancer-Associated Thrombosis – Lost in Translation Alok Khorana (US)  Dr. Lee presented on behalf of Dr. Khorana, who was unable to attend due to a family emergency.The controversial recommendations recently published in the 2012 ACCP guidelines on the prevention and treatment of cancer-associated thrombosis were reviewed.A discussion followed regarding whether a formal response from the subcommittee is warranted and in what format to express the concerns.There was general agreement that the ACCP guidelines do not reflect the opinions and standard of practice of physicians and experts in this field and a recommendation/proposal was made that the subcommittee should prepare guidance documents to outline controversial management issues.  Updates on clinical trials and registries Agnes Lee (CA), Sam Schulman (CA), Pieter Kamphuisen (NL), Marc Carrier (CA), Jeff Zwicker (US)  A rapid review of ongoing trials in cancer-associated thrombosis was presented by various investigators.Dr. Marc Carrier summarized the activities of the SOME study.This is an open randomized study investigating the utility of aggressive screening vs. limited screening in detection of occult cancer in patients presenting with unprovoked VTE.The primary endpoint is detection of occult malignancy.53% of the target sample size of 860 study patients has been reached.Dr. Lee presented on behalf of Dr. Simon Noble an update on the FRAGMATIC study.This is a randomized phase III study evaluating the effect of dalteparin in addition to chemotherapy on survival and disease progression in patients with primary lung cancer.Target sample size of 2203 has been reached and results are expected in 2013.Dr. Lee presented on behalf of Dr. Guy Meyer the design and activities of the TILT study.This open, randomized trial is studying the effect of adjuvant tinzaparin on survival in patients with completely resected stage I, II or IIIa non-small cell lung cancer.Total of 450 of 550 patients have been recruited.Enrolment is expected to complete in Jul 2013.Dr. Jeff Zwicker gave a brief review of the MicoTEC study.The results were presented during the "Hot Topics” session of the conference.This phase II study showed that enoxaparin showed a strong trend in lowering the incidence of DVT detected by screening ultrasound at Day 60 in patients with high levels of TF microparticles.Dr. Zwicker also presented the design of the phase II MicroSTAT study evaluating the role of rosuvastatin in lowering circulating TF microparticles in women with metastatic breast cancer.Dr. Khorana’s PHACS study was presented by Dr. Lee.Patients with a high Khorana score (3 or higher) were randomized to receive dalteparin or no treatment for primary prophylaxis.Recently the blinded data were analyzed by the FDA and the target sample size has been reduced due to higher than expected rate of VTE.The results of the study are anticipated in 1.5 years.Dr. Kamphuisen updated the activities of the LONGHEVA trial.This study is evaluating whether LMWH is superior to vitamin K antagonists in cancer patients who have already received 6 – 12 months of anticoagulant therapy for VTE.32 patients have been enrolled and the trial is facing difficulty with recruitment.Dr. Lee presented on the CATCH trial, a multinational, phase III study comparing tinzaparin with warfarin for treatment of cancer-associated thrombosis.The study has enrolled 1/3 of the target sample size of 900 patients and has received recommendation by the Data Monitoring and Safety Board to continue.Dr. Sam Schulman gave an update on the international registry on recurrent venous thromboembolism in anticoagulated patients with cancer. Currently 151 patients have been recruited, 200 is the target. Some baseline data were presented. New sites are still welcome to join.  New Proposals and Hypotheses  Prothrombotic state and metastasis in preclinical models Wolfrum Ruf (US)  Dr. Ruf presented his laboratory’s work on elucidating the mechanisms of metastasis.Tumor cell tissue factor (TF)-initiated coagulation supports fibrin formation, platelet activation, and monocyte/macrophage recruitment and thereby contributes to the survival of lodged metastases in the lung vasculature. Recent studies identified host anticoagulant mechanisms as a major impediment for successful hematogenous tumor cell metastasis. We addressed the contributions of host hemostatic factors and of thrombin signaling through protease activated receptor (PAR) 1 to the markedly enhanced metastasis in hyperthrombotic thrombomodulin mutant (TMPro) mice. In this model, full-length TF- and platelet-dependent, but contact pathway-independent syngeneic breast cancer metastasis was not significantly reduced following fibrinogen depletion, pharmacological blockade of monocyte adhesion receptors for platelets, or genetic deletion of platelet glycoprotein Iba. Mice with very low levels of the endothelial protein C receptor did not phenocopy the enhanced metastasis phenotype of TMPro mice. Similarly, genetic deletion of PAR1 that is not expressed by mouse platelets did not diminish enhanced metastasis in TMPro mice. Experiments with breast cancer cells derived from PAR1-deficient mice furthermore excluded that thrombin-PAR1 signaling has major redundant prometastatic effects on tumor cells and the host. Thus, metastasis in the hyperthrombotic TMPro mouse model is largely independent of intravascular thrombin-PAR1 signaling, and primarily enhanced by increased tumor cell survival mediated by platelets.  Role of genetic polymorphisms in thrombosis and colorectal cancer Carla Vossen (NL)  Dr. Vossen presented and discussed her work on the association between 6 genetic variants in coagulation- or thrombosis-related genes and colorectal cancer risk or progression. The 6 genetic variants werefactor V Leiden,prothrombin G20210A, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, fibrinogen gamma (FGG) 10034C>T, factor XIII Val34Leu and methylenetetra-hydrofolate reductase (MTHFR) 677C>T. These variants were genotyped in 1801 colorectal cancer cases and 1853 controls from the DACHS study (Darmkrebs: Chancen der Verhütung durch Screening). Follow-up information for 1322 cases on cancer progression (recurrences and mortality) demonstrated an effect on colorectal cancer risk for factor V Leiden, prothrombin G20210A and factor XIII Val34Leu, and an effect on colorectal cancer-specific mortality for PAI-1 4G/5G and FGG 10034C>T. Future plans to further investigate the role of coagulation gene variants and colorectal cancer survival were presented.  Biomarkers in clinical practice Cihan Ay (AU)  Dr. Ay presented an overview and update of biomarker work in the Vienna Cancer and Thrombosis Study (CATS).In addition to previous the biomarkers which have shown an association with cancer-associated thrombosis, including platelet count, soluble P-selectin, factor VIII activity, prothrombin fragment 1+2 and D-dimer, thrombin generation has been found to be predictive of thrombotic complications.In contrast, an association between microparticle-associated tissue factor activity and VTE was not found. It was highlighted that further work is needed to re-analyze the data on previously identified markers using competitive risk methodology.  Competing risks in oncology trials Jeff Zwicker (US)  Dr. Zwicker discussed the methodologies used for analyzing VTE incidence in oncology trials.It is now recognized that competing risk analysis is most appropriate statistical methodology to evaluate the probability of VTE in cancer studies. In clinical trials that include patients with advanced malignancy, death is considered a competing risk for thrombosis due to its high incidence. Because VTE and death are unlikely to be independent events in these patients, the Kaplan and Meier approach to assessing the cumulative incidence of VTE is inappropriate because it ignores the effect of death as competing risk and thus overestimates the incidence of VTE. Gray’s test should be utilized to compare cumulative incidence rates of VTE between two or more groups when competing risks are present.This recommendation has been incorporated into the position paper on standardizing the definition, analysis reporting, of VTE in oncology trials.  Registry on incidental PE Marcello DiNisio (IT)  Dr. DiNisio presented on the rationale and design of a multicenter, international, prospective registry on the treatment of incidental pulmonary embolism (PE).Clinically unsuspected PE represents a common finding in cancer patients. Current guidelines suggest the same initial and long-term anticoagulation as for patients with symptomatic PE which in most cases implies indefinite treatment. These recommendations rely, however, on expert opinion in the absence of solid studies.The aim of this registry is to evaluate the current treatment approaches for unsuspected PE and to assess their efficacy and safety in a large prospective cohort of ambulatory or hospitalized cancer patients. The main outcomes are recurrent (symptomatic) PE or deep vein thrombosis, bleeding, and mortality. Follow-up visits are scheduled at 3 and 6 months after inclusion with a visit or phone contact at 12 months. A total of about 500 patients will be recruited in approximately 40 centers. Outcomes will be adjudicated by a central adjudication committee. An electronic case report form will be used for data collection. Dr. DiNisio also presented a cohort study to evaluate the efficacy and safety of a prophylactic dose of LMWH in preventing recurrent VTE in cancer patients with isolated subsegmental PE.There was strong support for both of these studies by the subcommittee.  New Oral Anticoagulants in CAT Agnes Lee (CA)  Dr. Lee presented a brief overview of the phase III data on the efficacy and safety of the new oral anticoagulants for the treatment of acute VTE.Limitations and concerns regarding the use of these new agents in cancer patients were outlined, including the paucity of clinical trial evidence, the potential for unpredictable bioavailability because of mucosal breakdown of the GI tract, the higher risk of GI bleeding reported in phase III studies, drug interaction with some chemotherapeutic agents, and the lack of an antidote.Further research with phase III/IV clinical trials focusing on cancer patients was strongly encouraged and received unanimous support.The challenges of trial designs and the necessity of industry support were discussed. A recommendation was made for a position paper by the subcommittee to highlight these issues.  The meeting was adjourned at 1300.
by A. Lee
Friday, September 14, 2012
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