International Journal of Hematology

, Volume 107, Issue 1, pp 92–97 | Cite as

Evaluation of the dose and efficacy of ruxolitinib in Japanese patients with myelofibrosis

  • Keita Kirito
  • Shinichiro Okamoto
  • Kohshi Ohishi
  • Tetsuzo Tauchi
  • Hiroshi Handa
  • Shigeki Saito
  • Katsuto Takenaka
  • Kazuya Shimoda
  • Kenji Oritani
  • Koichi Akashi
  • Hikaru Okada
  • Taro Amagasaki
  • Kazuyuki Suzuki
  • Toshio Yonezu
  • Norio Komatsu
Original Article


Ruxolitinib, a potent JAK1/JAK2 inhibitor, improved splenomegaly and myelofibrosis-associated symptoms and prolonged survival compared with placebo and best available therapy in the phase 3 COMFORT studies. Although cytopenias were the most common adverse events associated with ruxolitinib treatment, a COMFORT-I analysis showed that they were managed effectively with dose modifications, without a negative impact on the efficacy of ruxolitinib. Subsequently, studies A2202 and AJP01 showed that ruxolitinib is an effective treatment for Japanese patients with myelofibrosis. We conducted a pooled analysis of these two studies (N = 81) to evaluate the association between ruxolitinib dose and changes in spleen volume or symptoms in Japanese patients. Most patients began treatment at 15 or 20 mg twice daily (BID); 70% received a final titrated dose ≥ 10 mg BID. Overall, 91% of patients exhibited spleen volume reductions; patients with final titrated doses ≥ 10 mg BID had larger spleen volume reductions. Similarly, 83% of patients showed improvements in symptom scores; those with a final titrated dose of 20 or 25 mg BID had the greatest reductions. Consistent with COMFORT-I, this pooled analysis indicates that, despite dose adjustments, ruxolitinib provides spleen and symptom control in Japanese patients, with higher doses associated with better responses.


Myelofibrosis JAK inhibitor Ruxolitinib Japanese patients 



Editorial assistance was provided by Karen Chinchilla, PhD, of ArticulateScience LLC and was funded by Novartis Pharma KK.

Compliance with ethical standards

Conflict of interest

KK reports personal fees from Novartis Pharma KK, during conduct of the study. K. Shimoda reports grants and personal fees from Novartis Pharma KK, outside the submitted work. K. Oritani reports personal fees for lectures and scholarship contributions from Novartis Pharma KK, outside the submitted work. HO, TA, K Suzuki, and TY are employees of Novartis Pharma KK. SO, K. Ohishi, TT, HH, SS, KT, KA, and NK have no conflicts of interest to disclose.


  1. 1.
    Tefferi A. Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89(9):915–25.CrossRefPubMedGoogle Scholar
  2. 2.
    Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition, pathogenesis, and treatment. Annu Rev Med. 2009;60:233–45.CrossRefPubMedGoogle Scholar
  3. 3.
    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(13):2895–901.CrossRefPubMedGoogle Scholar
  4. 4.
    James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–90.CrossRefPubMedGoogle Scholar
  6. 6.
    Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–61.CrossRefPubMedGoogle Scholar
  7. 7.
    Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387–97.CrossRefPubMedGoogle Scholar
  8. 8.
    Tefferi A. Mutations galore in myeloproliferative neoplasms: would the real Spartacus please stand up? Leukemia. 2011;25(7):1059–63.CrossRefPubMedGoogle Scholar
  9. 9.
    Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Rumi E, Pietra D, Guglielmelli P, Bordoni R, Casetti I, Milanesi C, et al. Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms. Blood. 2013;121(21):4388–95.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–90.CrossRefPubMedGoogle Scholar
  12. 12.
    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(25):2391–405.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    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(9):787–98.CrossRefPubMedGoogle Scholar
  15. 15.
    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015;100(4):479–88.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    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(25):4047–53.CrossRefPubMedGoogle Scholar
  17. 17.
    Harrison CN, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Gisslinger H, Knoops L, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701–7.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Verstovsek S, Gotlib J, Gupta V, Atallah E, Mascarenhas J, Quintas-Cardama A, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther. 2013;7:13–21.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    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(7):2067–74.CrossRefPubMedGoogle Scholar
  20. 20.
    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(3):295–304.CrossRefPubMedGoogle Scholar
  21. 21.
    Komatsu N, Kirito K, Shimoda K, Ishikawa T, Ohishi K, Ohyashiki K, et al. Assessing the safety and efficacy of ruxolitinib in a multicenter, open-label, study in Japanese patients with myelofibrosis. Int J Hematol. 2017;105:309–17.CrossRefPubMedGoogle Scholar
  22. 22.
    Mesa RA, Gotlib J, Gupta V, Catalano JV, Deininger MW, Shields AL, et al. Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2013;31(10):1285–92.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365–76.CrossRefPubMedGoogle Scholar
  24. 24.
    Vannucchi AM, Kantarjian HM, Kiladjian JJ, Gotlib J, Cervantes F, Mesa RA, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase 3 trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015;100(9):1139–45.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2017

Authors and Affiliations

  • Keita Kirito
    • 1
  • Shinichiro Okamoto
    • 2
  • Kohshi Ohishi
    • 3
  • Tetsuzo Tauchi
    • 4
  • Hiroshi Handa
    • 5
  • Shigeki Saito
    • 6
    • 7
  • Katsuto Takenaka
    • 8
  • Kazuya Shimoda
    • 9
  • Kenji Oritani
    • 10
  • Koichi Akashi
    • 11
  • Hikaru Okada
    • 12
  • Taro Amagasaki
    • 12
  • Kazuyuki Suzuki
    • 12
  • Toshio Yonezu
    • 12
  • Norio Komatsu
    • 13
  1. 1.Department of Hematology and OncologyUniversity of YamanashiChuou-shiJapan
  2. 2.Division of Hematology, Department of MedicineKeio University HospitalTokyoJapan
  3. 3.Blood Transfusion ServiceMie University HospitalMieJapan
  4. 4.Department of HematologyTokyo Medical UniversityTokyoJapan
  5. 5.Department of MedicineGunma University HospitalGunmaJapan
  6. 6.Department of HematologyNagoya University HospitalNagoyaJapan
  7. 7.Department of Hematology and OncologyJapanese Red Cross Nagoya Daini HospitalAichiJapan
  8. 8.Center for Cellular and Molecular MedicineKyushu University HospitalFukuokaJapan
  9. 9.Department of Gastroenterology and HematologyUniversity of MiyazakiMiyazakiJapan
  10. 10.Department of Hematology and OncologyOsaka UniversityOsakaJapan
  11. 11.Department of Medicine and Biosystemic ScienceKyushu UniversityFukuokaJapan
  12. 12.Novartis Pharma KKTokyoJapan
  13. 13.Department of HematologyJuntendo University School of MedicineTokyoJapan

Personalised recommendations