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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Best Pract Res Clin Haematol · Jun 2013
ReviewNew anticoagulants in the treatment of patients with cancer-associated venous thromboembolism.
Venous thromboembolism (VTE) represents a common source of morbidity and mortality among patients with malignant disease. In this specific setting, the treatment of VTE is challenging as cancer patients display a high tendency to develop recurrent VTE, as well as anticoagulant-related bleeding complications. Low-molecular-weight heparins have been demonstrated to be more effective in the long-term prevention of recurrent VTE in cancer patients compared with conventional treatment with vitamin K antagonists. ⋯ Over the past decade, several novel oral anticoagulants have emerged, which can be administered in fixed doses without the need for monitoring. Clinical trials evaluating these agents for treatment in the general VTE population yielded promising results. This review summarizes the current management of cancer-associated VTE, overviews the trials that investigated the novel anticoagulant drugs for the treatment of acute VTE and discusses the potential of these novel agents for use in cancer patients.
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The new oral anticoagulants (NOACs) dabigatran etexilate, rivaroxaban, and apixaban have been extensively studied for prevention and treatment of venous thromboembolic disease and for stroke prevention in atrial fibrillation. Elderly patients have the highest incidence of thrombotic complications but also have the highest risk of anticoagulant associated bleeding. In this review we critically examine the balance between risks and benefits of NOACs compared with vitamin K antagonists in elderly patients enrolled in phase 3 randomized controlled trials for the management of venous thrombosis and stroke prevention in atrial fibrillation. Results show that the favourable balance between risks and benefits of NOACs is preserved in the elderly population.