title: Ruxolitinib leads to improvement of pulmonary hypertension in patients with myelofibrosis.
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.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tabarroki
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lindner
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: V
authors.initials: V
authors.lastname: Visconte
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Rogers
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Parker
authors.affiliation: Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: H K
authors.initials: HK
authors.lastname: Duong
authors.affiliation: Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lichtin
authors.affiliation: Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Kalaycio
authors.affiliation: 1] Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA [2] Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: Department of Cardiology, North Shore University Hospital, Manhasset, NY, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Mountantonakis
authors.affiliation: Department of Medicine, Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Heresi
authors.affiliation: 1] Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA [2] Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Tiu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D005293:Ferritins / Q000097:blood; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D009570:Nitriles; D055728:Primary Myelofibrosis / Q000097:blood / Q000150:complications* / Q000235:genetics; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines
chemical_list: D015415:Biomarkers; D016207:Cytokines; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D009569:Nitric Oxide; C540383:ruxolitinib; D005293:Ferritins; D053612:Janus Kinases