Myelofibrosis (MF) includes primary MF and MF that\u00a0has arisen from an antecedent polycythemia vera (PV) or\u00a0essential thrombocythemia (ET) (post-PV\/ET MF). MF\u00a0can affect patients in various ways, including progressive\u00a0splenomegaly, cytopenias (particularly anemia), and troublesome constitutional symptoms, including night sweats,\u00a0fevers, unintentional weight loss, or debilitating fatigue.\u00a0MF also can result in blastic transformation and death.<\/p>\n
Splenomegaly in MF patients can be a major independent source of morbidity and a detriment to their quality of\u00a0life.\u00a0It is sometimes massive (>10 kg) and can lead to\u00a0pain, early satiety, bloating, or even portal hypertension.\u00a0The bulk of the spleen can result in areas of ischemia and\u00a0painful episodes of splenic infarction, and splenic sequestration in splenomegaly can lead to the development or\u00a0exacerbation of cytopenias.<\/p>\n
Management of MF-associated splenomegaly can be\u00a0difficult, and the questions that arise represent a microcosm\u00a0of the management issues for MF in general. What are the\u00a0treatment goals for an individual patient\u2014cure or palliation? Who should receive an allogeneic stem cell transplant? What are the benefits of current medical therapies?\u00a0How do I manage the myelosuppression brought about by\u00a0medical therapy? Which patients should be considered for\u00a0splenectomy or splenic radiation? What is the impact of\u00a0experimental drugs (particularly the JAK2 inhibitors) on\u00a0splenomegaly, and would my patient benefit from treatment\u00a0with one of these agents? Each of these questions\u2014the key\u00a0challenges for hematologists involved in treating patients\u00a0with MF\u2014is addressed below.<\/p>\n
New Drugs and Their Impact on Myelofibrosis Therapy<\/p>\n
A key moment for the understanding\u2014and potentially the\u00a0treatment\u2014of MF occurred in 2005 with the heavily\u00a0publicized discovery of the JAK2V617F mutation.\u00a0Subsequently, additional genetic mutations with potential\u00a0pathogenetic implications for MF were found, including the\u00a0c-MPLW515L\/K (in 5% of primary MF and 1% of ET),\u00a0and somatic mutations in TET2 were identified in about\u00a015% of myeloid neoplasms (MPNs), an event preceding the\u00a0JAK2 mutation in MPN patients. Additional insights\u00a0recently gained through single nucleotide polymorphism\u00a0analysis suggest that both variability in other genes, or\u00a0perhaps even inherited haplotypes, may play a role in MPN\u00a0pathogenesis. Although the past 5 years have seen\u00a0significant advances in the understanding of MF pathophysiology, the therapies being investigated for the condition\u00a0involve building on prior efficacious drug therapies (IMiDs),\u00a0extrapolating from treatments for other chronic myeloid\u00a0disorders such as MDS, or using targeted approaches (JAK2\u00a0inhibitors).<\/p>\n
JAK2 Inhibitors Current management of symptomatic splenomegaly in MF\u00a0patients requires thoughtful consideration of prognosis and\u00a0treatment goals. For those who are not candidates for\u00a0transplantation, the palliative benefit of current therapies\u00a0must be balanced against the potential risks and benefits of\u00a0experimental therapies. The JAK2 inhibitors have created\u00a0great excitement among those treating MF patients because\u00a0of their targeted approach. Preliminary data indicate a\u00a0meaningful response for MF patients in terms of symptomatic splenomegaly. However, although the JAK2 inhibitors\u00a0have provided a valuable incremental benefit over previous\u00a0options, particularly for symptoms and quality of life, they\u00a0have not yet demonstrated a significant impact on anemia\u00a0or more advanced disease features. Future advances for MF\u00a0patients may require further vetting of current and future\u00a0JAK2 inhibitors, trials of JAK2 inhibitors combined with\u00a0other agents (such as an IMiD against anemia), or further\u00a0advances in our understanding of the pathogenesis of the\u00a0disorder, to open additional avenues for targeted therapies.<\/p>\n <\/p>\n Ruben A. Mesa. Curr Hematol Malig Rep (2010) 5:15\u201321<\/p>\n Myelofibrosis (MF) includes primary MF and MF that\u00a0has arisen from an antecedent polycythemia vera (PV) or\u00a0essential thrombocythemia (ET) (post-PV\/ET MF). MF\u00a0can affect patients in various ways, including progressive\u00a0splenomegaly, cytopenias (particularly […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[273,274,268,269,267,272],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/493"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=493"}],"version-history":[{"count":1,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/493\/revisions"}],"predecessor-version":[{"id":494,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/493\/revisions\/494"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=493"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=493"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=493"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
\nVarious therapeutic strategies are being developed to try to\u00a0block the proliferative stimulus associated with these MPN\u00a0associated mutations. Current testing using these inhibitors\u00a0can be divided into three groups: preclinical testing (based\u00a0on in vitro activity against cells containing JAK2V617F),\u00a0ongoing testing in murine models, and testing in clinical\u00a0trials. Between 10 and 20 agents with reported in vitro or\u00a0murine-model activity are in the pipeline, but we\u00a0will focus on those agents in which clinical activity has\u00a0already been reported in the public forum. JAK2 inhibition\u00a0clinical results can be divided into two categories of agents:\u00a0novel small molecules designed and tested for specificity\u00a0and selectivity against JAK2 (INCB018424<\/a>, XL019<\/a>,\u00a0TG101348<\/a>, SB1518<\/a>, CYT387<\/a>), and agents that inhibit a\u00a0variety of kinases including JAK2 (ITF2357, CEP-701)<\/p>\nReference:<\/h4>\n
Related Products:<\/h4>\n
<\/th> <\/th> <\/th> <\/th><\/tr><\/thead> CAS Number <\/td> Product Name <\/td> Molecular Formula <\/td> Molecular Weight <\/td><\/tr> 1092939-15-5 <\/td> INCB018424<\/a><\/td> C21H22N6O4 <\/td> 422.44 <\/td><\/tr> 936091-26-8 <\/td> XL019<\/a><\/td> C25H28N6O2 <\/td> 444.53 <\/td><\/tr> 936091-26-8 <\/td> TG101348<\/a><\/td> C27H36N6O3S <\/td> 524.68 <\/td><\/tr> 937272-79-2 <\/td> Pacritinib<\/a><\/td> C28H32N4O3 <\/td> 472.58 <\/td><\/tr> 1160597-06-7 <\/td> CYT-387<\/a><\/td> C23H22N6O2 <\/td> 414.46 <\/td><\/tr><\/tbody><\/table><\/div>\n","protected":false},"excerpt":{"rendered":"