ABSTRACT
Before activated kinases were discovered as the causative events in BCR-ABL -negative myeloproliferative disorders (MPD), patients with MPD were treated primarily with the intention to relieve symptoms and/or to prevent complications. 1-3 As discussed in the previous chapters, cytoreduction by hydroxyurea was shown to be beneficial in preventing thrombotic complications in patients with essential thrombocythemia (ET) who were considered to be ‘high-risk ’ (age > 60 years and/or previous thrombosis). 4 The Primary Thrombocythemia1 (PT-1) study 5 showed that hydroxyurea plus aspirin was more effective in reducing thrombotic complications than anagrelide plus aspirin in high-risk ET patients. These differences were pronounced for arterial thromboses, but not for venous thromboses, where patients on anagrelide plus aspirin fared better. 5 The European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study 6 recently provided a rational basis for the use of lowdose aspirin in the prevention thrombotic of complications in MPD and dissipated the fears of increasing morbidity and mortality from hemorrhagic events linked to the use of aspirin in these patients. These studies are currently the pillars for evidence-based therapeutic decisions. Although the latter results were obtained by studying patients with polycythemia vera (PV), it is now common practice to give aspirin also to patients with ET and during the cellular phase of primary myelofibrosis (PMF). 3 Interferon alfa (IFN α ) showed promise as an alternative drug that could replace hydroxyurea in the management of MPD, but the high rate of unwanted side-effects limits its potential
for long-term applications. 2,3 Thus, the therapeutic options in MPD are limited and new drugs are in demand. Particularly in young patients with ET or PV we are faced with difficult decisions, for which no data from controlled studies are available. The uncertainty concerning potential leukemogenic effects of hydroxyurea7-9 weighs even more heavily in young patients with MPD, since the therapy once initiated is usually continued life-long. In advanced stages of PMF, allogeneic stem cell transplantation has been shown to be effective in some cases. 10,11 Whether reduced intensity conditioning regimens or standard conditioning should be used and the criteria for identifying patients who will benefit most from this form of therapy are currently the subject of further studies. The discovery of activating mutations in the Janus kinase 2 ( JAK2 ) gene that can be found in the majority of patients with PV, ET, and PMF, 12-15 and the involvement of other kinases, such as platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) in rare forms of MPD, raised the hope that kinase inhibitors may soon become first-line therapy in MPD patients. Here, we primarily discuss the prospects of inhibitors of JAK2 and related downstream signaling molecules. The vast majority of patients with MPD carry a G > T transversion in exon 14 of JAK2 that changes a valine in position 617 to a phenylalanine ( JAK2 V617F). 12-15 Recently, mutations in exon 12 of the JAK2 gene have been found in PV patients who are negative for JAK2 V617F. 16 These exon 12 mutations alter various nucleotide positions in the vicinity of codon 539 and frequently also involve deletions of 1 – 3 codons. Most of the patients studied had mutations at slightly
trast to the uniform pattern of JAK2 V617F. In cell lines, the exon 12 mutations led to stronger activation of the JAK2 activity than the JAK2 V617F mutation. Recently, mutations in position 515 of MPL gene that change the wild-type tryptophane to leucine (W515L) or lysine (W515K) have been found in 1 % of patients with ET and 5 % of patients with PMF. 17,18 These mutations render MPL signaling independent of ligand binding, but JAK2 activity is required to transmit the signals. Thus, inhibitors of JAK2 can be expected to be effective both in patients with activating JAK2 mutations and with activating MPL mutations.
