International Journal of Hematology

, Volume 105, Issue 3, pp 309–317 | Cite as

Assessing the safety and efficacy of ruxolitinib in a multicenter, open-label study in Japanese patients with myelofibrosis

  • Norio KomatsuEmail author
  • Keita Kirito
  • Kazuya Shimoda
  • Takayuki Ishikawa
  • Kohshi Ohishi
  • Kazuma Ohyashiki
  • Naoto Takahashi
  • Hikaru Okada
  • Taro Amagasaki
  • Toshio Yonezu
  • Koichi Akashi
Original Article


Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated durable improvements in splenomegaly, symptoms, and overall survival in controlled clinical trials in patients with myelofibrosis. The single-arm study reported here was initiated to collect further safety and efficacy data in Japanese patients with myelofibrosis and is the largest study of ruxolitinib in this population. The primary objective was to assess safety. Secondary endpoints included changes in spleen size and patient-reported outcomes. The primary analysis occurred when all patients (N = 51) completed 24 weeks or discontinued. Overall, 86.3% of patients completed treatment; 9.8% discontinued due to adverse events (AEs). Consistent with previous studies, the most common AEs were anemia (62.7%) and thrombocytopenia (29.4%). Furthermore, levels of select immunologic biomarkers remained stable, and no deaths occurred. At week 24, 30.0% of evaluable patients experienced ≥50% reductions from baseline in palpable spleen length; 26.0% had ≥35% reductions in spleen volume. Additionally, ruxolitinib led to clinically significant improvements in symptoms and quality of life. Overall, findings from this study indicate that ruxolitinib is safe and effective in Japanese patients with myelofibrosis, with these benefits extending to patients with intermediate-1–risk myelofibrosis and to those with low platelet counts.


Myelofibrosis Ruxolitinib Japanese patients 



Osaka University Hospital, Kenji Oritani; Gunma University Hospital, Hiroshi Handa; Kyusyu University Hospital, Katsuto Takenaka; Jichi Medical University Hospital, Tadashi Nagai; Medical Hospital of Tokyo Medical and Dental University, Tetsuya Fukuda; Tokyo Women’s Medical University Hospital, Junji Tanaka; Nippon Medical School Hospital, Koichi Inokuchi; Kurume University Hospital, Koji Nagafuji; Kobe University Hospital, Hironobu Minami; Nagasaki University Hospital, Tomoko Hata; Kinki University Hospital, Itaru Matsumura; Kumamoto University Hospital, Yuji Yonemura; Ehime University Hospital, Jun Yamanouchi; Tohoku University Hospital, Kenichi Ishizawa; Tokyo Metropolitan Komagome Hospital, Kazuteru Ohashi; Hokkaido University Hospital, Takanori Teshima; Kyoto University Hospital, Akifumi Takaori; Kansai Medical University Hirakata Hospital, Shinya Fujita; Okayama University Hospital, Mitsune Tanimoto; Sapporo Medical University Hospital, Tsutomu Sato; Matsuyama Red Cross Hospital, Tomoaki Fujisaki; Nagoya City University Hospital, Sinsuke Iida; Gifu University Hospital, Hisashi Tsurumi. Editorial assistance was provided by John Togneri, PhD, and was funded by Novartis Pharma KK.

Compliance with ethical standards

Conflicts of interest

TI., K. Ohishi, and K. Ohyashiki have nothing to disclose. N.K. has participated in advisory boards and speakers bureau for Novartis Pharma KK. K.K. has received honoraria from Novartis Pharma KK: K.S. has received honoraria from and has been a consultant for Novartis Pharma KK. N.T. has received grants from Novartis Pharma KK, Pfizer, Daiichi Sankyo, Kyowa Hakko Kirin Co., Ltd., Fujimoto Pharmaceutical, Otsuka Pharmaceutical, Toyama Chemical, Chugai, Asahi Kasei, and Eisai and personal fees from Novartis Pharma KK, Pfizer, Kyowa Hakko Kirin Co., Ltd., and Otsuka Pharmaceutical. H.O., T.A., and T.Y. are employees of Novartis Pharma KK. K.A. has received research funding and participated in speakers bureau for Asahi Kasei, Shionogi, Astellas, Celgene, Chugai, Bristol-Myers Squibb, Kyowa Hakko Kirin Co., Ltd., and Novartis Pharma KK. and has been a consultant for Kyowa Hakko Kirin Co., Ltd., and Novartis Pharma KK.

Supplementary material

12185_2016_2130_MOESM1_ESM.docx (153 kb)
Supplementary material 1 (DOCX 152 kb)


  1. 1.
    Tefferi A. Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89:915–25.CrossRefPubMedGoogle Scholar
  2. 2.
    Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia. 2008;22:905–14.CrossRefPubMedGoogle Scholar
  3. 3.
    Scherber RM, Dueck AC, Johansson P, Barbui T, Barosi G, Vannucchi AM, et al. Symptomatic burden in myelofibrosis (MF): prospective international assessment in 128 MF patients. J Clin Oncol. 2011;29(suppl) [abstract 6610].Google Scholar
  4. 4.
    Mesa RA, Niblack J, Wadleigh M, Verstovsek S, Camoriano J, Barnes S, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer. 2007;109:68–76.CrossRefPubMedGoogle Scholar
  5. 5.
    Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition, pathogenesis, and treatment. Annu Rev Med. 2009;60:233–45.CrossRefPubMedGoogle Scholar
  6. 6.
    Tefferi A. Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013;88:141–50.CrossRefPubMedGoogle Scholar
  7. 7.
    Mesa RA, Schwager S, Radia D, Cheville A, Hussein K, Niblack J, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res. 2009;33:1199–203.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    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;113:2895–901.CrossRefPubMedGoogle Scholar
  9. 9.
    Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA. New mutations and pathogenesis of myeloproliferative neoplasms. Blood. 2011;188:1723–35.CrossRefGoogle Scholar
  10. 10.
    Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cazzola M, Kralovics R. From Janus kinase 2 to calreticulin: the clinically relevant genomic landscape of myeloproliferative neoplasms. Blood. 2014;123:3714–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799–807.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787–98.CrossRefPubMedGoogle Scholar
  14. 14.
    Cervantes F, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Sirulnik A, Stalbovskaya V, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013;122:4047–53.CrossRefPubMedGoogle Scholar
  15. 15.
    Jung CW, Shih LY, Xiao Z, Jie J, Hou HA, Du X, et al. Efficacy and safety of ruxolitinib in Asian patients with myelofibrosis. Leuk Lymphoma. 2015;56:2067–74.CrossRefPubMedGoogle Scholar
  16. 16.
    Oritani K, Okamoto S, Tauchi T, Saito S, Ohishi K, Handa H, et al. A multinational, open-label, phase 2 study of ruxolitinib in Asian patients with myelofibrosis: Japanese subset analysis. Int J Hematol. 2015;101:295–304.CrossRefPubMedGoogle Scholar
  17. 17.
    Talpaz M, Paquette R, Afrin L, Hamburg SI, Prchal JT, Jamieson K, et al. Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. J Hematol Oncol. 2013;6:81.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Mead AJ, Milojkovic D, Knapper S, Garg M, Chacko J, Farquharson M, et al. Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST Trial. Br J Haematol. 2015;170:29–39.CrossRefPubMedGoogle Scholar
  19. 19.
    Davis KL, Côté I, Kaye JA, Mendelson E, Goa H, Perez Ronco J. Real-world assessment of clinical outcomes in patients with lower-risk myelofibrosis receiving treatment with ruxolitinib. Adv Hematol. 2015;2015:848473.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Giraldo P, Palandri F, Palumbo GA, Zaritskey A, Calistri E, Skotnicki A, et al. Safety and efficacy of ruxolitinib (RUX) in patients with Intermediate-1–risk myelofibrosis (MF) from an open-label, multicenter, single-arm expanded-access study. Haematologica. 2015;100(suppl 1) [abstract P675].Google Scholar
  21. 21.
    Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.CrossRefPubMedGoogle Scholar
  22. 22.
    Tavares R, Palumbo GA, LeCoutre P, Palandri F, Al-Ali H, Martino B, et al. Safety and efficacy of ruxolitinib in an 1869-patient cohort of JUMP: an open-label, multicenter, single-arm, expanded-access study in patients with myelofibrosis. Blood. 2015;126 [abstract 2799].Google Scholar
  23. 23.
    Palandri F, Polverelli N, Catani L, Vianelli N. Ruxolitinib-associated tuberculosis: a case of successful ruxolitinib rechallenge. Ann Hematol. 2015;94:519–20.CrossRefPubMedGoogle Scholar
  24. 24.
    Chen YH, Lee CH, Pei SN. Pulmonary tuberculosis reactivation following ruxolitinib treatment in a patient with primary myelofibrosis. Leuk Lymphoma. 2015;56:1528–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Shen CH, Hwang CE, Chen YY, Chen CC. Hepatitis B virus reactivation associated with ruxolitinib. Ann Hematol. 2013;93:1075–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Goldberg RA, Reichel E, Oshry LJ. Bilateral toxoplasmosis retinitis associated with ruxolitinib. N Engl J Med. 2013;369:681–3.CrossRefPubMedGoogle Scholar
  27. 27.
    Wathes R, Moule S, Milojkovic D. Progressive multifocal leukoencephalopathy associated with ruxolitinib. N Engl J Med. 2013;369:197–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel Janus kinase 1,2 inhibitor. Chest. 2013;143:1478–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Lee SC, Feenstra J, Georghiou PR. Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy. BMJ Case Rep. 2014;2:2014.Google Scholar
  30. 30.
    Hultcrantz M, Lund SH, Andersson TM, Björkholm M, Kristinsson S. Myeloproliferative neoplasms and infections; a population-based study on 9,665 patients with myeloproliferative neoplasms diagnosed in Sweden 1987–2009. Haematologica. 2015;100(suppl 1) [abstract P666].Google Scholar
  31. 31.
    Polverelli N, Breccia M, Benevolo G, Latagliata R, Catani L, Perricone M, et al. Unfavorable karyotype and molecular negativity significantly influence the infectious risk in myelofibrosis: evaluation on 426 patients. Haematologica. 2015;100(suppl 1) [abstract P667].Google Scholar
  32. 32.
    Heine A, Held SA, Daecke SN, Wallner S, Parampalli Yajnanarayana S, Kurts C, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013;122:1192–202.CrossRefPubMedGoogle Scholar
  33. 33.
    Massa M, Rosti V, Campanelli R, Fois G, Barosi G. Rapid and long-lasting decrease of T-regulatory cells in patients with myelofibrosis treated with ruxolitinib. Leukemia. 2014;28:449–51.CrossRefPubMedGoogle Scholar
  34. 34.
    Schönberg K, Rudolph J, Cornez I, Brossart P, Wolf D. The JAK1/JAK2 inhibitor ruxolitinib substantially affects NK cell biology. Blood. 2013;122 [abstract 16].Google Scholar
  35. 35.
    Griesshammer M, Vannucchi A, le Coutre P, Tavares R, Al-Ali H, Raanani P, et al. Safety and efficacy of ruxolitinib in patients with low platelets enrolled in a phase 3b expanded-access study in myelofibrosis (MF). Blood. 2014;124 [abstract 1859].Google Scholar

Copyright information

© The Japanese Society of Hematology 2016

Authors and Affiliations

  • Norio Komatsu
    • 1
    Email author
  • Keita Kirito
    • 2
  • Kazuya Shimoda
    • 3
  • Takayuki Ishikawa
    • 4
  • Kohshi Ohishi
    • 5
  • Kazuma Ohyashiki
    • 6
  • Naoto Takahashi
    • 7
  • Hikaru Okada
    • 8
  • Taro Amagasaki
    • 8
  • Toshio Yonezu
    • 8
  • Koichi Akashi
    • 9
  1. 1.Department of HematologyJuntendo University School of Medicine, Juntendo UniversityTokyoJapan
  2. 2.Department of Hematology and OncologyUniversity of YamanashiYamanashiJapan
  3. 3.Department of Gastroenterology and HematologyUniversity of MiyazakiMiyazakiJapan
  4. 4.Department of HematologyKobe City Medical Center General HospitalKobeJapan
  5. 5.Blood Transfusion ServiceMie UniversityTsuJapan
  6. 6.Department of HematologyTokyo Medical UniversityTokyoJapan
  7. 7.Department of HematologyNephrology, and Rheumatology, Akita University Graduate School of MedicineAkitaJapan
  8. 8.Novartis Pharma KKTokyoJapan
  9. 9.Department of Medicine and Biosystemic ScienceKyushu UniversityFukuokaJapan

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