JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations

Leukemia. 2011 Feb;25(2):218-25. doi: 10.1038/leu.2010.269. Epub 2010 Nov 16.

Abstract

The discovery of JAK2V617F has rejuvenated interest in Janus kinase (JAK)-signal transducer and activator of transcription (STAT), both as an oncogenic pathway and a drug target in BCR-ABL1-negative myeloproliferative neoplasms (MPN). However, the complexity of these diseases in terms of both clonal structure and mutation repertoire makes it unlikely that JAK inhibitor therapy will replicate what has been achieved with imatinib in chronic myeloid leukemia. Consistent with this view, JAK inhibitor therapy in myelofibrosis has not yet produced complete or partial remissions. However, most patients treated with a JAK2 (TG101348) or JAK1/2 (INCB018424) inhibitor experienced substantial improvement in constitutional symptoms and reduction in spleen size; the mechanism of action for INCB018424 includes anti-JAK1-mediated downregulation of proinflammatory cytokines. These observations complicate the choice of primary end points in clinical trials that would be robust enough to support regulatory approval. TG101348 and INCB018424 are the vanguard of JAK inhibitor therapy in myelofibrosis, but newer JAK inhibitors might have a broader spectrum of activity; preliminary results with CYT387 suggest responses in both anemia and splenomegaly. Outstanding issues regarding these drugs include identification of the optimal dosing strategy, their role (if any) in the treatment of polycythemia vera or essential thrombocythemia, and the potential for combining them with other therapeutic agents.

Publication types

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

MeSH terms

  • Humans
  • Janus Kinases / antagonists & inhibitors*
  • Myeloproliferative Disorders / drug therapy
  • Primary Myelofibrosis / drug therapy*
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazoles / therapeutic use
  • Pyrrolidines / therapeutic use
  • Sulfonamides / therapeutic use
  • Treatment Outcome

Substances

  • INCB018424
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrrolidines
  • Sulfonamides
  • Fedratinib
  • Janus Kinases