Best practice & research. Clinical haematology
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Agents targeting the JAK-STAT pathway have dominated the investigational therapeutic portfolio over the last five years resulting in the first and only approved agent for the treatment of patients with myelofibrosis (MF). However, chromatin modifying agents, anti-fibrosing agents, and other signaling pathway inhibitors have also demonstrated activity and offer the potential to improve upon the clinical success of JAK2 inhibition. Due to the complex pathobiological mechanisms underlying MF, it is likely that a combination of biologically active therapies will be required to target the MF hematopoietic stem cell in order to achieve significant disease course modification. ⋯ Ruxolitinib is also being incorporated in novel treatment strategies in the setting of hematopoietic stem cell transplantation for MF. As the pathogenetic mechanisms are better understood, potential drug combinations in MF will increase dramatically and demonstration of biologic activity in effective preclinical models will be required to efficiently evaluate the most active combinations with least toxicity in future trials. This manuscript will address the proposed goals of combination therapy approach and review the state of the art in combination experimental therapy for MF.
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Best Pract Res Clin Haematol · Jun 2014
ReviewHereditary erythrocytosis, thrombocytosis and neutrophilia.
Hereditary erythrocytosis, thrombocytosis, and neutrophilia are rare inherited syndromes which exhibit Mendelian inheritance. Some patients with primary hereditary erythrocytosis exhibit a mutation in the erythropoietin receptor (EPOR) which is associated with low serum erythropoietin (EPO) levels. Secondary congenital erythrocytosis may be characterized by normal or high serum EPO levels, and is related to high oxygen affinity haemoglobin variants, mutation of the enzyme biphosphoglycerate mutase (BPGM), or defects in components of the oxygen-sensing pathway. ⋯ More recently, germline mutations in JAK2, distinct from JAK2 V617F, and mutation of the gelsolin gene, were uncovered in several pedigrees of hereditary thrombocytosis. Hereditary neutrophilia has been described in one family with an activating germline mutation in CSF3R. The mutational basis for most hereditary myeloproliferative disorders has yet to be identified.
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Best Pract Res Clin Haematol · Sep 2013
ReviewAcute graft-versus-host disease: are we close to bringing the bench to the bedside?
Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (AHSCT) associated with significant morbidity and mortality. This review focuses on the pathophysiology, prevention, and treatment of acute GVHD. ⋯ Insights into the mechanisms of this disease relate directly to the development of preventive strategies and therapies, such as immunosuppression, calcineurin inhibitors, T-cell depletion, CCR5 antagonists, gut decontamination, extracorporeal photopheresis, and more. Understanding the immunobiology of GVHD and developing effective preventions and treatments are critical to the continuing success of AHSCT.
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In the past decade, several new oral anticoagulants (NOACs) have been studied and approved for the prophylaxis and treatment of arterial and venous thromboembolism. These agents were shown to be as effective as or better than warfarin and resulted in comparable or lower bleeding rates than warfarin. Specific antidotes for the reversal of the anticoagulant effect of these drugs, such as monoclonal antibodies against the direct thrombin inhibitor dabigatran or recombinant Xa-analog in the case of factor Xa inhibitors, are still being investigated in early clinical trials. ⋯ Activated prothrombin complex concentrate seems promising for the reversal of dabigatran, while non-activated prothrombin complex concentrates have potential for the reversal of anti-factor Xa. The risk of thromboembolic complications requires careful evaluation. In this article, the evidence- or the lack of it - supporting the use of the different prohemostatic agents for the management of bleeding and for reversal of the different classes of NOACs is discussed.
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Best Pract Res Clin Haematol · Jun 2013
ReviewNovel oral anticoagulants in secondary prevention of stroke.
In patients with atrial fibrillation (AF) oral anticoagulation with vitamin-K antagonists (warfarin, phenprocoumon) is effective both for primary and secondary stroke prevention yielding a 60-70% relative reduction in stroke risk compared with placebo, as well as a mortality reduction of 26 percent. Vitamin-K antagonists have a number of well documented shortcomings. Recently the results of randomised trials for three new oral anticoagulants that do not exhibit the limitations of vitamin-K antagonists have been published. ⋯ New anticoagulants add to the therapeutic options for patients with AF, and offer a number of advantages over warfarin, for both the clinician and patient, including a favorable bleeding profile and convenience of use. Aspirin is no longer an option in secondary stroke prevention in patients with atrial fibrillation. Consideration of these new anticoagulants will improve clinical decision making.