Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic Myeloproliferative Neoplasias

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Tabarroki A, Tiu RV . Immunomodulatory agents in myelofibrosis. Expert Opin Investig Drugs 2012; 21: 1141–1154.

    Article  CAS  PubMed  Google Scholar 

  2. Tefferi A, Lasho TL, Jimma T, Finke CM, Gangat N, Vaidya R et al. One thousand patients with primary myelofibrosis: the Mayo clinic experience. Mayo Clin Proc 2012; 87: 25–33.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cortelezzi A, Gritti G, Del Papa N, Pasquini MC, Calori R, Gianelli U et al. Pulmonary arterial hypertension in primary myelofibrosis is common and associated with an altered angiogenic status. Leukemia 2008; 22: 646–649.

    Article  CAS  PubMed  Google Scholar 

  4. Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009; 26 113: 2895–2901.

    Article  CAS  PubMed  Google Scholar 

  5. Guilpain P, Montani D, Damaj G, Achouh L, Lefrere F, Le Pavec J et al. Pulmonary hypertension associated with myeloproliferative disorders: a retrospective study of ten cases. Respiration 2008; 76: 295–302.

    Article  CAS  PubMed  Google Scholar 

  6. Krug S, Seyfarth HJ, Hagendorff A, Wirtz H . Inhaled iloprost for hepatopulmonary syndrome: improvement of hypoxemia. Eur J Gastroenterol Hepatol 2007; 19: 1140–1143.

    Article  PubMed  Google Scholar 

  7. Seyfarth HJ, Hammerschmidt S, Pankau H, Winkler J, Wirtz H . Long-term bosentan in chronic thromboembolic pulmonary hypertension. Respiration 2007; 74: 287–292.

    Article  CAS  PubMed  Google Scholar 

  8. Rubin LJ . Primary pulmonary hypertension. N Engl J Med 1997; 336: 111–117.

    Article  CAS  PubMed  Google Scholar 

  9. Hassell KL . Pulmonary hypertension, tricuspid regurgitant velocity screening, and the nitric oxide pathway. Hematology Am Soc Hematol Educ Program 2011; 2011: 419–426.

    Article  PubMed  Google Scholar 

  10. Hayes D Jr. . Idiopathic pulmonary arterial hypertension misdiagnosed as asthma. J Asthma 2007; 44: 19–22.

    Article  PubMed  Google Scholar 

  11. Runo JR, Loyd JE . Primary pulmonary hypertension. Lancet 2003; 361: 1533–1544.

    Article  PubMed  Google Scholar 

  12. Simonneau G . [A new clinical classification of pulmonary hypertension]. Bull Acad Natl Med 2009; 193: 1897–1909.

    PubMed  Google Scholar 

  13. Garcia-Manero G, Schuster SJ, Patrick H, Martinez J . Pulmonary hypertension in patients with myelofibrosis secondary to myeloproliferative diseases. Am J Hematol 1999; 60: 130–135.

    Article  CAS  PubMed  Google Scholar 

  14. Rostagno C, Prisco D, Abbate R, Poggesi L . Pulmonary hypertension associated with long-standing thrombocytosis. Chest 1991; 99: 1303–1305.

    Article  CAS  PubMed  Google Scholar 

  15. De Klippel N, Dehou MF, Bourgain C, Schots R, De Keyser J, Ebinger G . Progressive paraparesis due to thoracic extramedullary hematopoiesis in myelofibrosis. Case report. J Neurosurg 1993; 79: 125–127.

    Article  CAS  PubMed  Google Scholar 

  16. Mishchenko E, Tefferi A . Treatment options for hydroxyurea-refractory disease complications in myeloproliferative neoplasms: JAK2 inhibitors, radiotherapy, splenectomy and transjugular intrahepatic portosystemic shunt. Eur J Haematol 2010; 85: 192–199.

    Article  CAS  PubMed  Google Scholar 

  17. Shapiro SM, Oudiz RJ, Cao T, Romano MA, Beckmann XJ, Georgiou D et al. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol 1997; 30: 343–349.

    Article  CAS  PubMed  Google Scholar 

  18. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358: 1119–1123.

    Article  CAS  PubMed  Google Scholar 

  19. Ward AC, Touw I, Yoshimura A . The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood 2000; 95: 19–29.

    CAS  PubMed  Google Scholar 

  20. Vainchenker W, Favale F . Myelofibrosis JAK2 inhibitors and erythropoiesis. Leukemia 2013; 27: 1219–1223.

    Article  CAS  PubMed  Google Scholar 

  21. Walker JG, Smith MD . The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol 2005; 32: 1650–1653.

    CAS  PubMed  Google Scholar 

  22. Ananthakrishnan R, Hallam K, Li Q, Ramasamy R . JAK-STAT pathway in cardiac ischemic stress. Vascul Pharmacol 2005; 43: 353–356.

    Article  CAS  PubMed  Google Scholar 

  23. O'Shea JJ, Holland SM, Staudt LM . JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 2013; 368: 161–170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Masri FA, Xu W, Comhair SA, Asosingh K, Koo M, Vasanji A et al. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007; 293: 548–554.

    Article  Google Scholar 

  25. Deisseroth A, Kaminskas E, Grillo J, Chen W, Saber H, Lu HL et al. U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin Cancer Res 2012; 18: 3212–3217.

    Article  CAS  PubMed  Google Scholar 

  26. Verstovsek S . Ruxolitinib: an oral Janus kinase 1 and Janus kinase 2 inhibitor in the management of myelofibrosis. Postgrad Med 2013; 125: 128–135.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Keohane C, Mesa R, Harrison C . The role of JAK1/2 inhibitors in the treatment of chronic myeloproliferative neoplasms. Am Soc Clin Oncol Educ Book 2013; 2013: 301–305.

    Article  Google Scholar 

  28. Mesa RA, Shields A, Hare T, Erickson-Viitanen S, Sun W, Sarlis NJ et al. Progressive burden of myelofibrosis in untreated patients: assessment of patient-reported outcomes in patients randomized to placebo in the COMFORT-I study. Leuk Res 2013; 16: 1–6.

    Google Scholar 

  29. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54 (1 Suppl): S55–S66.

    Article  PubMed  Google Scholar 

  30. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society Inc., and the Pulmonary Hypertension Association. Circulation 2009; 119: 2250–2294.

    Article  PubMed  Google Scholar 

  31. Kiatchoosakun S, Wongvipaporn C, Nanagara R, Hoit BD . Right ventricular systolic pressure assessed by echocardiography: a predictive factor of mortality in patients with scleroderma. Clin Cardiol 2011; 34: 488–493.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sarkar R, Gelabert HA, Mohiuddin KR, Thakor DK, Santibanez-Gallerani AS . Effect of cigarette smoke on endothelial regeneration in vivo and nitric oxide levels. J Surg Res 1999; 82: 43–47.

    Article  CAS  PubMed  Google Scholar 

  33. Barua RS, Ambrose JA, Srivastava S, DeVoe MC, Eales-Reynolds LJ . Reactive oxygen species are involved in smoking-induced dysfunction of nitric oxide biosynthesis and upregulation of endothelial nitric oxide synthase: an in vitro demonstration in human coronary artery endothelial cells. Circulation 2003; 107: 2342–2347.

    Article  CAS  PubMed  Google Scholar 

  34. Jenkins DJ, Kendall CW, Marchie A, Parker TL, Connelly PW, Qian W et al. Dose response of almonds on coronary heart disease risk factors: blood lipids, oxidized low-density lipoproteins, lipoprotein(a), homocysteine, and pulmonary nitric oxide: a randomized, controlled, crossover trial. Circulation 2002; 106: 1327–1332.

    Article  CAS  PubMed  Google Scholar 

  35. Choi JW, Pai SH, Kim SK, Ito M, Park CS, Cha YN . Iron deficiency anemia increases nitric oxide production in healthy adolescents. Ann Hematol 2002; 81: 1–6.

    Article  CAS  PubMed  Google Scholar 

  36. Odemis E, Koca C, Karadag A, Catal F, Aydin M, Turkay S et al. Nitric oxide affects serum ferritin levels in children with iron deficiency. Pediatr Hematol Oncol 2007; 24: 189–194.

    Article  CAS  PubMed  Google Scholar 

  37. Sudarma V, Sukmaniah S, Siregar P . Effect of dark chocolate on nitric oxide serum levels and blood pressure in prehypertension subjects. Acta Med Indones 2011; 43: 224–228.

    PubMed  Google Scholar 

  38. Dishy V, Sofowora G, Harris PA, Kandcer M, Zhan F, Wood AJ et al. The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men. Clin Pharmacol Ther 2001; 70: 270–279.

    Article  CAS  PubMed  Google Scholar 

  39. Gelosa P, Cimino M, Pignieri A, Tremoli E, Guerrini U, Sironi L . The role of HMG-CoA reductase inhibition in endothelial dysfunction and inflammation. Vasc Health Risk Manag 2007; 3: 567–577.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhao YY, Liu Y, Stan RV, Fan L, Gu Y, Dalton N et al. Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proc Natl Acad Sci USA 2002; 99: 11375–11380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Qi Y, Jamindar TM, Dawson G . Hypoxia alters iron homeostasis and induces ferritin synthesis in oligodendrocytes. J Neurochem 1995; 64: 2458–2464.

    Article  CAS  PubMed  Google Scholar 

  42. Rhodes CJ, Wharton J, Wilkins MR . Pulmonary hypertension: biomarkers. Handb Exp Pharmacol 2013; 218: 77–103.

    Article  CAS  PubMed  Google Scholar 

  43. Ataga KI, Moore CG, Jones S, Olajide O, Strayhorn D, Hinderliter A et al. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol 2006; 134: 109–115.

    Article  PubMed  Google Scholar 

  44. Machado RF, Anthi A, Steinberg MH, Bonds D, Sachdev V, Kato GJ et al. N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. JAMA 2006; 296: 310–318.

    Article  CAS  PubMed  Google Scholar 

  45. Van Beers EJ, Nur E, Schaefer-Prokop CM, Mac Gillavry MR, van Esser JW, Brandjes DP et al. Cardiopulmonary imaging, functional and laboratory studies in sickle cell disease associated pulmonary hypertension. Am J Hematol 2008; 83: 850–854.

    Article  PubMed  Google Scholar 

  46. Voskaridou E, Tsetsos G, Tsoutsias A, Spyropoulou E, Christoulas D, Terpos E . Pulmonary hypertension in patients with sickle cell/beta thalassemia: incidence and correlation with serum N-terminal pro-brain natriuretic peptide concentrations. Haematologica 2007; 92: 738–743.

    Article  CAS  PubMed  Google Scholar 

  47. Njaman W, Iesaki T, Iwama Y, Takasaki Y, Daida H . Serum uric acid as a prognostic predictor in pulmonary arterial hypertension with connective tissue disease. Int Heart J 2007; 48: 523–532.

    Article  CAS  PubMed  Google Scholar 

  48. Jing ZC, Jiang X, Wu BX, Xu XQ, Wu Y, Ma CR et al. Vardenafil treatment for patients with pulmonary arterial hypertension: a multicentre, open-label study. Heart 2009; 95: 1531–1536.

    Article  CAS  PubMed  Google Scholar 

  49. Ulrich S, Fischler M, Speich R . Update on therapies for pulmonary hypertension. Swiss Med Wkly 2007; 137: 73–82.

    CAS  PubMed  Google Scholar 

  50. Zharikov S, Krotova K, Hu H, Baylis C, Johnson RJ, Block ER et al. Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Physiol Cell Physiol 2008; 295: C1183–C1190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lopes AA, Barreto AC, Maeda NY, Cicero C, Soares RP, Bydlowski SP et al. Plasma von Willebrand factor as a predictor of survival in pulmonary arterial hypertension associated with congenital heart disease. Braz J Med Biol Res 2011; 44: 1269–1275.

    Article  CAS  PubMed  Google Scholar 

  52. Andreassen AK, Wergeland R, Simonsen S, Geiran O, Guevara C, Ueland T . N-terminal pro-B-type natriuretic peptide as an indicator of disease severity in a heterogeneous group of patients with chronic precapillary pulmonary hypertension. Am J Cardiol 2006; 98: 525–529.

    Article  CAS  PubMed  Google Scholar 

  53. Zharikov SI, Swenson ER, Lanaspa M, Block ER, Patel JM, Johnson RJ . Could uric acid be a modifiable risk factor in subjects with pulmonary hypertension? Med Hypotheses 2010; 74: 1069–1074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jung YJ, Isaacs JS, Lee S, Trepel J, Neckers L . IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J 2003; 17: 2115–2117.

    Article  CAS  PubMed  Google Scholar 

  55. Dimitroulas T, Giannakoulas G, Dimitroula H, Sfetsios T, Parcharidou D, Karvounis H et al. Significance of serum uric acid in pulmonary hypertension due to systemic sclerosis: a pilot study. Rheumatol Int 2011; 31: 263–267.

    Article  CAS  PubMed  Google Scholar 

  56. Collados MT, Sandoval J, Lopez S, Masso FA, Paez A, Borbolla JR et al. Characterization of von Willebrand factor in primary pulmonary hypertension. Heart Vessels 1999; 14: 246–252.

    Article  CAS  PubMed  Google Scholar 

  57. Schmitt A, Jouault H, Guichard J, Wendling F, Drouin A, Cramer EM . Pathologic interaction between megakaryocytes and polymorphonuclear leukocytes in myelofibrosis. Blood 2000; 96: 1342–1347.

    CAS  PubMed  Google Scholar 

  58. Marxsen JH, Stengel P, Doege K, Heikkinen P, Jokilehto T, Wagner T et al. Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-alpha-prolyl-4-hydroxylases. Biochem J 2004; 381: 761–767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ichinose F, Roberts JD Jr., Zapol WM . Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential. Circulation 2004; 109: 3106–3111.

    Article  PubMed  Google Scholar 

  60. Riddell DR, Owen JS . Nitric oxide and platelet aggregation. Vitam Horm 1999; 57: 25–48.

    Article  CAS  PubMed  Google Scholar 

  61. Demoncheaux EA, Higenbottam TW, Kiely DG, Wong JM, Wharton S, Varcoe R et al. Decreased whole body endogenous nitric oxide production in patients with primary pulmonary hypertension. J Vasc Res 2005; 42: 133–136.

    Article  CAS  PubMed  Google Scholar 

  62. Kaneko FT, Arroliga AC, Dweik RA, Comhair SA, Laskowski D, Oppedisano R et al. Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am J Respir Crit Care Med 1998; 158: 917–923.

    Article  CAS  PubMed  Google Scholar 

  63. Chan ED, Riches DW . IFN-gamma+LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38(mapk) in a mouse macrophage cell line. Am J Physiol Cell Physiol 2001; 280: C441–C450.

    Article  CAS  PubMed  Google Scholar 

  64. Singh K, Balligand JL, Fischer TA, Smith TW, Kelly RA . Regulation of cytokine-inducible nitric oxide synthase in cardiac myocytes and microvascular endothelial cells. Role of extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and STAT1 alpha. J Biol Chem 1996; 271: 1111–1117.

    Article  CAS  PubMed  Google Scholar 

  65. Takaki H, Minoda Y, Koga K, Takaesu G, Yoshimura A, Kobayashi T . TGF-beta1 suppresses IFN-gamma-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation. Genes Cells 2006; 11: 871–882.

    Article  CAS  PubMed  Google Scholar 

  66. Wang C, Yang F, Xu Z, Shi D, Chen D, Dai J et al. Intravenous release of NO from lipidic microbubbles accelerates deep vein thrombosis resolution in a rat model. Thromb Res 2013; 131: e31–e38.

    Article  CAS  PubMed  Google Scholar 

  67. Fang C, Stavrou E, Schmaier AA, Grobe N, Morris M, Chen A et al. Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2-/- mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation. Blood 2013; 121: 3023–3032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ling Y, Johnson MK, Kiely DG, Condliffe R, Elliot CA, Gibbs JS et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med 2012; 186: 790–796.

    Article  PubMed  Google Scholar 

  69. Verstovsek S, Kantarjian HM, Estrov Z, Cortes JE, Thomas DA, Kadia T et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood 2012; 120: 1202–1209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A . Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J Clin Oncol 2011; 29: 1356–1363.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in full or partially by Cleveland Clinic Seed Support, American Cancer Society, Scott Hamilton CARES grant (RVT) and Athymic Animal and Xenograft Core Facility (NIH/NCI P30 CA043703-23 (DL)).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R V Tiu.

Ethics declarations

Competing interests

RVT is on the Speaker’s bureau of INCYTE. The remaining authors declare no conflict of interest.

Additional information

Author contributions

AT conducted experiments, analyzed the data and wrote the manuscript; DJL provided scientific advice and measured the NO levels; VV performed experiments and edited the manuscript; LZ analyzed statistical data; HJR performed the vWB and RCA measurements and edited the manuscript; YP assisted with mice experiments; HKD contributed patients and edited the manuscript; AL, MEK, MAS contributed patients and edited the manuscript; SEM provided expertise on echocardiographic findings and edited the manuscript; GAH provided expertise on PH, edited the manuscript and provided scientific advice; RVT conceived and designed the study, analyzed the data, and wrote the manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tabarroki, A., Lindner, D., Visconte, V. et al. Ruxolitinib leads to improvement of pulmonary hypertension in patients with myelofibrosis. Leukemia 28, 1486–1493 (2014). https://doi.org/10.1038/leu.2014.5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2014.5

Keywords

This article is cited by

Search

Quick links