Summary Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at an increased risk of developing VTE and are more likely to have a recurrence ...of VTE and bleeding while taking anticoagulants. Management of VTE in patients with cancer is a major therapeutic challenge and remains suboptimal worldwide. In 2013, the International Initiative on Thrombosis and Cancer (ITAC-CME), established to reduce the global burden of VTE in patients with cancer, published international guidelines for the treatment and prophylaxis of VTE and central venous catheter-associated thrombosis. The rapid global adoption of direct oral anticoagulants for management of VTE in patients with cancer is an emerging treatment trend that needs to be addressed based on the current level of evidence. In this Review, we provide an update of the ITAC-CME consensus recommendations based on a systematic review of the literature ranked according to the Grading of Recommendations Assessment, Development, and Evaluation scale. These guidelines aim to address in-hospital and outpatient cancer-associated VTE in specific subgroups of patients with cancer.
Cancer‐associated thrombosis (CAT) is a major cause of morbidity and mortality in patients with cancer. Over the past 2 decades, enormous advances have been made in the management of CAT. The growing ...evidence base informing practice has led to the publication of a number of guidelines and guidance documents on the diagnosis and treatment of CAT. The goal of this review is to examine the latest versions of evidence‐based guidelines, highlighting the differences and similarities in their methodology, their disease‐specific content, and recommendations for management. Our analysis shows that for most clinical topics, the different guidelines provide roughly similar management advice. However, there are a number of important clinical topics in CAT that are not currently covered by the existing guidelines. We think inclusion of these topics in future versions of the guidelines will facilitate ongoing efforts to optimize the care of patients with CAT.
Implications for Practice
Cancer‐associated thrombosis (CAT) is a common complication in patients with cancer. This review examines the differences and similarities of the current CAT guidelines methods and recommendations. Current guidelines largely agree on many aspects of CAT management. However, there are a number of topics in CAT that are not currently included in guidelines where evidence‐based guidance would be very helpful for clinicians. Coverage of these topics in future guidelines is encouraged to optimize clinical practice.
Numerous guidelines for cancer‐associated thromboembolism have been published. This review compares recommendations from the most recent cancer‐specific guidelines, identifying areas in which guidance is lacking.
Symptomatic venous thromboembolism (VTE) occurs 4-7 times more frequently in cancer patients as compared to non-cancer patients. A significant number of risk factors, which can be subcategorised as ...patient-, cancer- or treatment-related, have been shown to influence the risk of VTE during malignancy and further incorporated in risk-assessment models. Safe and efficient thromboprophylaxis regimens allow substantial decreased in VTE rates, since VTE is most often a largely preventable disease, but thromboprophylaxis remains underused in cancer compared to non-cancer patients. If thromboprophylaxis is warranted in cancer patients undergoing surgery or hospitalised for acute medical illness or with a lower mobility in the absence of contraindications to anticoagulants, its benefit remains controversial in outpatients and may be limited to locally advanced or metastatic pancreatic or lung cancer treated with chemotherapy. The International Initiative on Thrombosis and Cancer-CME free mobile app (ios and android), based on the International Clinical Practice Guidelines (CPG), facilitates their implementation and dissemination of knowledge worldwide so as to improve VTE treatment and prophylaxis in cancer patients.
Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients and leads to a significant increase in health care costs. Cancer patients often suffer from multiple ...co-morbidities and have both a greater risk of VTE recurrence and bleeding compared to non-cancer patients. Anticoagulation is therefore challenging. For many years, long-term therapy with Low-Molecular-Weight Heparin (LMWH) was the standard of care for the management of cancer-associated VTE. Direct oral anticoagulants (DOAC), which offer the convenience of an oral administration and have a rapid onset of action, have recently been proposed as a new option in this setting. Head-to-head comparisons between DOAC and LMWHs for the treatment of established VTE are now available, and data on the efficacy and safety of these drugs for primary prophylaxis of VTE in ambulatory cancer patients receiving systemic anticancer therapy are emerging. This narrative review aims to summarize the main recent advances in the prevention and treatment of cancer-associated VTE, including recent data on the use of individualized factors to stratify the risk of VTE in each individual patient, quality-of-life in patients treated with LMWH, and the place that DOACs will likely take in the cancer-associated VTE management landscape.
With accumulating evidence and improved outcomes along with recognition that modern biological therapies are not universally effective, require chronic administration and have high acquisition costs, ...hematopoietic stem cell transplantation (HSCT) has become an emerging direction for cell therapy in autoimmune diseases (ADs). The goal of this therapy is to induce medication-free remissions by resetting the immune system into a naïve and self-tolerant state through eradication of the autoreactive immunologic memory and profound re-configuration of the immune system induced by the transplant procedure. Safety of HSCT has generally improved by implementing internal quality management and external accreditation. Inter-disciplinary guidelines for patient selection, transplant technique and supportive care along with greater center experience should optimize safe and appropriate delivery of HSCT in specific ADs. In this review, we discuss the current role and future perspectives of HSCT in AD, focusing on recent published clinical and scientific studies and recommendations in the field.
Concept of hematopoietic stem cell therapy in autoimmune diseases. A) An autoreactive immunologic memory may drive chronic autoimmune responses and represents a major barrier for curative therapeutic approaches in autoimmunity. Once developed, autoreactive memory cells migrate into inflamed tissues where they reside as tissue-resident memory cells, e.g. CNS-infiltrating T-cells in MS after crossing the blood-brain-barrier, kidney-infiltrating T-cells in SLE, skin-resident T-cells in systemic sclerosis or synovial T-cells in inflammatory arthritis. Likewise, autoreactive memory T-cells and plasma cells migrate into the bone marrow where they survive in dedicated survival niches. B) Current therapeutic concepts are historically based on chronic suppression of immune functions either with conventional immunosuppression or by targeting inflammatory cytokines, co-stimulatory signals or adhesion molecules. However, the autoreactive immunologic memory is largely unresponsive to these approaches. C) In contrast, hematopoietic stem cell transplantation is performed with the premise to eradicate autoreactive memory clones using chemotherapeutic agents usually in combination with polyclonal antibodies such as anti-thymocyte globulin (ATG) for in vivo T-cell depletion. D) Transplanted autologous HSC promote an extensive immune renewal providing a new and polyclonal repertoire of naïve T- and B-cells and a novel protective immunologic memory is generated. As a consequence, restoration of self-tolerance may be achieved resulting in long-term remissions that are not further dependent on chronic immune suppression. Display omitted
•HSCT has the potential to induce sustained clinical remissions in autoimmune diseases (AD) by restoring self-tolerance.•The majority of procedures are autologous HSCT, with an evolving base in MS, systemic sclerosis and Crohn’s disease.•The principle of HSCT is based on depletion of the pathogenic autoreactive repertoire and enabling immunologic renewal.•Immunologic renewal provides a diverse repertoire of naïve T- and B-cells, including restoration of regulatory cells.•HSCT requires careful patient selection and multidisciplinary team working between hematology and AD specialists.
Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This ...European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124.
Autologous hematopoietic stem cell transplantation has been used since 1996 for the treatment of severe autoimmune diseases refractory to approved therapies. We evaluated the long-term outcomes of ...these transplants and aimed to identify potential prognostic factors.
In this observational study we analyzed all first autologous hematopoietic stem cell transplants for autoimmune diseases reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 1996-2007. The primary end-points for analysis were overall survival, progression-free survival and transplant-related mortality at 100 days.
Nine hundred patients with autoimmune diseases (64% female; median age, 35 years) who underwent a first autologous hematopoietic stem cell transplant were included. The main diseases were multiple sclerosis (n=345), systemic sclerosis (n=175), systemic lupus erythematosus (n=85), rheumatoid arthritis (n=89), juvenile arthritis (n=65), and hematologic immune cytopenia (n=37). Among all patients, the 5-year survival was 85% and the progression-free survival 43%, although the rates varied widely according to the type of autoimmune disease. By multivariate analysis, the 100-day transplant-related mortality was associated with the transplant centers' experience (P=0.003) and type of autoimmune disease (P=0.03). No significant influence of transplant technique was identified. Age less than 35 years (P=0.004), transplantation after 2000 (P=0.0015) and diagnosis (P=0.0007) were associated with progression-free survival.
This largest cohort studied worldwide shows that autologous hematopoietic stem cell transplantation can induce sustained remissions for more than 5 years in patients with severe autoimmune diseases refractory to conventional therapy. The type of autoimmune disease, rather than transplant technique, was the most relevant determinant of outcome. Results improved with time and were associated with the transplant centers' experience. These data support ongoing and planned phase III trials to evaluate the place of autologous hematopoietic stem cell transplantation in the treatment strategy for severe autoimmune diseases.
Allogeneic mesenchymal stem/stromal cells (MSCs) have been widely studied as an alternative cell source for regenerative medicine. Here, we report a long-term follow-up study of allogeneic bone ...marrow and/or umbilical cord MSC transplantation (MSCT) in severe and drug-refractory systemic lupus erythematosus (SLE) patients. Eighty-one patients were enrolled, and the 5-year overall survival rate was 84% (68/81) after MSCT. At 5-year follow-up, 27% of patients (22/81) were in complete clinical remission and another 7% (6/81) were in partial clinical remission, with a 5-year disease remission rate of 34% (28/81). In total, 37 patients had achieved clinical remission and then 9 patients subsequently relapsed, with 5-year overall rate of relapse of 24% (9/37). SLE Disease Activity Index scores, serum albumin, complement C3, peripheral white blood cell, and platelet numbers, as well as proteinuria levels, continued to improve during the follow-up. Our results demonstrated that allogeneic MSCT is safe and resulted in long-term clinical remission in SLE patients.
•Mesenchymal stem/stromal cell therapy shows a 5-year survival rate of 84% for lupus•34% of refractory lupus patients are in clinical remission after cell therapy•Mesenchymal stem/stromal cell treatment ameliorates multi-organ function in lupus
In this article, Sun and colleagues show that allogeneic bone marrow and/or umbilical cord-derived mesenchymal stem/stromal cell transplantation both result in good clinical safety and effect in treating drug-refractory systemic lupus erythematosus patients, by introducing a 5- to 8-year follow-up study for all the 81 enrolled patients.
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