title: Drug Development Pipeline for Myeloproliferative Neoplasms: Potential Future Impact on Guidelines and Management.
abstract: The unprecedented success of ruxolitinib in myelofibrosis (MF) has paved the way for the development of other Janus kinase (JAK) inhibitors and other agents representing diverse drug classes and mechanisms of action in myeloproliferative neoplasms (MPNs). In particular, the symptomatic benefits afforded by ruxolitinib have led to the recognition of "clinical improvement" in symptoms and the spleen in international consensus response criteria for MF. Ruxolitinib is also approved for the second-line treatment of polycythemia vera and is being developed for essential thrombocythemia. Appreciation of the universal role of activated JAK/signal transducer and activator of transcription (STAT) signaling in MPNs and improved understanding of the canonical and noncanonical actions of JAK2 have yielded a number of drug targets beyond JAK2 in MPNs, which form the basis for a number of ruxolitinib-based rational combinations that are being explored in MF. Other JAK inhibitors with the potential for significantly less myelosuppression or even improvement of anemia continue to be tested. Finally, agents with very distinct mechanisms of action, such as novel interferon formulations, antifibrotic agents, and telomerase inhibitors, are being pursued in polycythemia vera and MF, respectively. This article reviews the current landscape of clinical drug development in MPNs, focusing on the most promising agents and combinations.
authors.affiliation: From The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Prithviraj
authors.initials: P
authors.lastname: Bose
authors.affiliation: From The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
mesh_terms: D002986:Clinical Trials as Topic; D015195:Drug Design; D004359:Drug Therapy, Combination; D006401:Hematologic Agents / Q000627:therapeutic use; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends; D009570:Nitriles; D010677:Philadelphia Chromosome; D011087:Polycythemia Vera / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D017410:Practice Guidelines as Topic; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use; D011743:Pyrimidines; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013920:Thrombocythemia, Essential / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality
chemical_list: D006401:Hematologic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050791:STAT Transcription Factors; C540383:ruxolitinib; D053612:Janus Kinases