Ruxolitinib leads to improvement of pulmonary hypertension in patients with myelofibrosis

Leukemia. 2014 Jul;28(7):1486-93. doi: 10.1038/leu.2014.5. Epub 2014 Jan 10.

Abstract

Pulmonary hypertension (PH) is a frequently under recognized complication of myelofibrosis (MF). The pathophysiology of PH in MF is unknown and no definitive therapies have been established. We studied 15 patients with MF-associated PH and compared their echocardiographic and PH relevant biomarkers (nitric oxide (NO), N-terminal pro-hormone of brain natriuretic peptide (NT-pro BNP), von Willebrand antigen (vWB), ristocetin-cofactor activity (RCA) and uric acid (UA)) pre- and post-ruxolitinib treatment. Ruxolitinib decreased the plasma levels of NT-pro BNP (73%; P=0.043), UA (60%), vWB (86%) and RCA (73%; P=0.036). Improvements in echocardiographic findings were also seen in 66% of patients (P=0.022). Furthermore, marked increase in NO compared with baseline (69.75 vs 40.1 picomolar (pM); P=0.001) was observed post-ruxolitinib therapy, whereas no changes were noted with conventional therapies. Treatment with ruxolitinib also resulted in the reduction of key cytokines (tumor necrosis factor alpha, interleukin-4 (IL-4), IL-6 and IL-8) and induction of interferon-gamma. Animal studies further supported the role of ruxolitinib in the induction of NO levels. In conclusion, aberrant Janus kinase (JAK)-signal transducer and activator of transcription signaling in MF may mediate PH through dysregulation of NO and cytokine levels, which can be restored by therapy with JAK inhibitors suggesting that inhibition of this pathway is a novel target for the management of patients with PH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Biomarkers / blood
  • Cytokines / blood
  • Disease Models, Animal
  • Echocardiography
  • Female
  • Ferritins / blood
  • Humans
  • Hypertension, Pulmonary / diagnosis
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / etiology*
  • Janus Kinases / antagonists & inhibitors
  • Male
  • Mice, Knockout
  • Middle Aged
  • Nitric Oxide / blood
  • Primary Myelofibrosis / blood
  • Primary Myelofibrosis / complications*
  • Primary Myelofibrosis / genetics
  • Pyrazoles / therapeutic use*

Substances

  • Biomarkers
  • Cytokines
  • INCB018424
  • Pyrazoles
  • Nitric Oxide
  • Ferritins
  • Janus Kinases