Best practice & research. Clinical haematology
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The discovery of the activating mutation JAK2 V617F ushered a new era in MPN which included new diagnostic and prognostic criteria as well as a potential therapeutic target. JAK2 inhibition became a reality with first patients receiving drugs that targeted JAK2 in 2007 and was marked by the first approval in 2011 of Ruxolitinib a JAK 1 and 2-inhibitor to treat myelofibrosis (MF). ⋯ Reflecting upon what we have learnt from the chronic myeloid leukaemia field and for MF regarding disease complexity as well as individual patient factors including resistance we discuss why it is likely we will need several different agents with JAK inhibitory activity. The next chapter discusses combination therapies for myelofibrosis which is a logical step in both trying to cure this disease and improve patient outcome and toxicities with JAK inhibitors.
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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.