The role of JAK1/2 inhibitors in the treatment of chronic myeloproliferative neoplasms

Am Soc Clin Oncol Educ Book. 2013;301-5. doi: 10.14694/EdBook_AM.2013.33.301.

Abstract

In 2005, the description of the JAK2V617F mutation for the first time provided a molecular key to enable more rapid diagnosis and target for novel therapeutics in the myeloproliferative neoplasms. In 2007, the first-in-class agent INC18424, ruxolitinib, JAKafi, or JAKAVI was first tested in patients with intermediate-risk 2 or high-risk myelofibrosis regardless of whether they possessed the JAK2V617F mutation. Patients treated with this agent had major reduction in splenomegaly as well as impressive reduction, and in some cases resolution, of symptoms. This study was followed by the two Controlled Myelofibrosis Study with Oral JAK Inhibitor Therapy (COMFORT) trials (the first-ever phase III trials in myelofibrosis), which confirmed results in these aspects were superior to either placebo or standard care, and updated results show a survival advantage with this therapy. This paper discusses these results and data from other JAK inhibitors while speculating on the future of these therapies. It also reflects on the fact that the true targets and agents' mode of action are uncertain. Unlike targeted therapy for chronic myeloid leukemia (CML), these agents do not deliver molecular remission, and it is not clear whether their predominant benefit is mediated via JAK2, JAK1, or both. Nonetheless, the advent of the JAK inhibitor is a welcome advance and has made a dramatic improvement to the therapeutic landscape of these conditions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Benzamides / therapeutic use
  • Bridged-Ring Compounds / therapeutic use
  • Humans
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / genetics
  • Molecular Targeted Therapy / methods
  • Mutation
  • Myeloproliferative Disorders / drug therapy*
  • Myeloproliferative Disorders / genetics
  • Myeloproliferative Disorders / mortality
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyrimidines / therapeutic use
  • Pyrrolidines / therapeutic use
  • Sulfonamides / therapeutic use

Substances

  • 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
  • Benzamides
  • Bridged-Ring Compounds
  • INCB018424
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Pyrrolidines
  • Sulfonamides
  • Fedratinib
  • N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2