Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and safety of rituximab in Japanese patients with acquired thrombotic thrombocytopenic purpura refractory to conventional therapy

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Thrombotic thrombocytopenic purpura (TTP), while rare, is a potentially life-threatening disorder. Plasma exchange (PE) is considered the primary treatment for TTP. In Western countries, rituximab, an anti-CD20 antibody, is recommended with PE for the treatment of refractory/relapsed TTP, and as up-front therapy in newly diagnosed TTP with neurological/cardiac pathology. The present open-label, single-arm, multicenter study evaluated the efficacy and safety of rituximab in Japanese patients with refractory/relapsed TTP. Patients received rituximab 375 mg/m2 intravenously, once weekly for a total of four treatments, with PE and steroids. Of six evaluable patients in the full analysis set, two met the primary efficacy endpoint (platelet count >150 × 109/L at week 4), yielding a 33.3 % response rate (95 % confidence interval: 4.3–77.7). While the lower confidence limit of the primary efficacy endpoint failed to reach the pre-specified threshold of 30 %, clinically significant recovery of platelet count with discontinuation of PE, increase of ADAMTS13 activity, disappearance of ADAMTS13 inhibitor, and improvement of TTP-associated clinical manifestations were observed after rituximab therapy in all patients. No safety concerns were identified in this study; therefore, rituximab is considered a useful treatment option in Japanese TTP patients who are refractory to conventional therapy.

Trial registration JMA-IIA00160.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Török TJ, Holman RC, Chorba TL. Increasing mortality from thrombotic thrombocytopenic purpura in the United States-analysis of national mortality data, 1968–1991. Am J Hematol. 1995;50:84–90.

    Article  PubMed  Google Scholar 

  2. Ministry of Health, Labour and Welfare. Patient survey by injury and disease. 2013. http://www.mhlw.go.jp/toukei/saikin/hw/kanja/10syoubyo/. Accessed 18 Jan 2016 (Internet).

  3. Matsumoto M, Bennett CL, Isonishi A, Qureshi Z, Hori Y, Hayakawa M, et al. Acquired idiopathic ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in a population from Japan. PLoS One. 2012;7:e33029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413:488–94.

    Article  CAS  PubMed  Google Scholar 

  5. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339:1584–94.

    Article  Google Scholar 

  6. Zheng XL, Wu HM, Shang D, Falls E, Skipwith CG, Cataland SR, et al. Multiple domains of ADAMTS13 are targeted by autoantibodies against ADAMTS13 in patients with acquired idiopathic thrombotic thrombocytopenic purpura. Haematologica. 2010;95:1555–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shimizu M, Nomura S, Ishii K, Mohri Y, Umei N, Fujiyama Y, et al. The significance of ADAMTS13 in a patient with thrombotic thrombocytopenic purpura complicated autoimmune hepatitis. Thromb Haemost. 2009;101:599–600.

    CAS  PubMed  Google Scholar 

  8. Tsai M. Pathophysiology of thrombotic thrombocytopenic purpura. Int J Hematol. 2010;91:1–19.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Scully M, Hunt BJ, Benjamin S, Liesner R, Rose P, Peyvandi F, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158:323–35.

    Article  PubMed  Google Scholar 

  10. Scully M, McDonald V, Cavenagh J, Hunt BJ, Longair I, Cohen H, et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acquired thrombotic thrombocytopenic purpura. Blood. 2011;118:1746–53.

    Article  CAS  PubMed  Google Scholar 

  11. Clark WF, Rock G, Barth D, Arnold DM, Webert KE, Yenson PR, et al. A phase-II sequential case-series study of all patients presenting to four plasma exchange centres with presumed relapsed/refractory thrombotic thrombocytopenic purpura treated with rituximab. Br J Haematol. 2015;170:208–17.

    Article  CAS  PubMed  Google Scholar 

  12. Tun NM, Villani GM. Efficacy of rituximab in acute refractory or chronic relapsing non-familial idiopathic thrombotic thrombocytopenic purpura: a systematic review with pooled data analysis. J Thromb Thrombolysis. 2012;34:347–59.

    Article  CAS  PubMed  Google Scholar 

  13. Soucemarianadin M, Benhamou Y, Delmas Y, Pichereau C, Maury E, Pène F, et al. Twice-daily therapeutical plasma exchange-based salvage therapy in severe autoimmune thrombotic thrombocytopenic purpura: the French TMA Reference Center experience. Eur J Haematol. 2015. doi:10.1111/ejh.12706.

    Google Scholar 

  14. Omri HE, Taha RY, Gamil A, Ibrahim F, Sabah HA, Mahmoud ZO, et al. Efficacy and safety of rituximab for refractory and relapsing thrombotic thrombocytopenic purpura: a cohort of 10 cases. Clin Med Insights Blood Disord. 2015;8:1–7.

    PubMed  PubMed Central  Google Scholar 

  15. Lim W, Vesely SK, Geoge JN. The role of rituximab in the management of patients with acquired thrombotic thrombocytopenic purpura. Blood. 2015;125:1526–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kato S, Matsumoto M, Matsuyama T, Isonishi A, Hiura H, Fujimura Y. Novel monoclonal antibody-based enzyme immunoassay for determining plasma levels of ADAMTS13 activity. Transfusion. 2006;46:1444–52.

    Article  CAS  PubMed  Google Scholar 

  17. Yagi H, Ito S, Kato S, Hiura H, Matsumoto M, Fujimura Y. Plasma levels of ADAMTS13 antigen determined with an enzyme immunoassay using a neutralizing monoclonal antibody parallel ADAMTS13 activity levels. Int J Hematol. 2007;85:403–7.

    Article  CAS  PubMed  Google Scholar 

  18. Scully M, Cohen H, Cavenagh J, Benjamin S, Starke R, Killick S, et al. Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13. Br J Haematol. 2007;136:451–61.

    Article  CAS  PubMed  Google Scholar 

  19. Kremer Hovinga JA, Vesely SK, Terrell DR, Lammle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115:1500–11.

    Article  PubMed  Google Scholar 

  20. Fakhouri F, Vernant JP, Veyradier A, Wolf M, Kaplanski G, Binaut R, et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood. 2005;106:1932–7.

    Article  CAS  PubMed  Google Scholar 

  21. Kosugi S, Matsumoto M, Ohtani Y, Take H, Ishizuka H, Kuyama J, et al. Rituximab provided long-term remission in a patient with refractory relapsing thrombotic thrombocytopenic purpura. Int J Hematol. 2005;81:433–6.

    Article  PubMed  Google Scholar 

  22. Ahmad A, Aggarwal A, Sharma D, Dave HP, Kinsella V, Rick ME, et al. Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP). Am J Hematol. 2004;77:171–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The drug and safety information were provided by Zenyaku Kogyo. We thank all patients, clinicians, and support staff who participated in this study. We are grateful to the following doctors: Hidekazu Ohta (Sapporo Hokuyu Hospital), Hiroshi Handa and Yoshiyuki Ogawa (Gunma University), Hidesaku Asakura (Kanazawa University), Shosaku Nomura (Kansai Medical University), Hideo Wada (Mie University), Kazuo Tsubaki (Kinki University), Satoshi Higasa (Hyogo Medical University). We are also grateful to the persons in charge of data collection and strategic support: Kazuo Watanabe and Fumiaki Kobayashi (CTD Co.,) and DOT International. Reiko Yamaura, J. Ludovic Croxford, PhD, and Marion Barnett, of Edanz Group Limited, provided medical writing support, which was funded by Zenyaku Kogyo.

Author information

Author notes

  1. Kazunori Imada

    Present address: Osaka Red Cross Hospital, Osaka, Japan

Authors and Affiliations

  1. Department of General Internal Medicine, Saitama Medical University, 38 Morohongo, Moroyamamachi, Irumagun, Saitama, 350-0495, Japan

    Yoshitaka Miyakawa

  2. Department of Hematology, Kokura Memorial Hospital, Fukuoka, Japan

    Kazunori Imada

  3. Department of Hematology and Oncology, Hiroshima University, Hiroshima, Japan

    Tatsuo Ichinohe

  4. Department of General Medicine, Nara Medical University, Nara, Japan

    Kenji Nishio

  5. Department of Preventive Medicine and Public Health, Biostatistics Unit at the Clinical and Translational Research Center, Keio University School of Medicine, Tokyo, Japan

    Takayuki Abe

  6. Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan

    Mitsuru Murata

  7. Department of Hematology/Oncology, Kurashiki Central Hospital, Okayama, Japan

    Yasunori Ueda

  8. Department of Blood Transfusion Medicine, Nara Medical University, Nara, Japan

    Yoshihiro Fujimura & Masanori Matsumoto

  9. Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

    Shinichiro Okamoto

Authors
  1. Yoshitaka Miyakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazunori Imada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tatsuo Ichinohe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenji Nishio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takayuki Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mitsuru Murata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasunori Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoshihiro Fujimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masanori Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shinichiro Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshitaka Miyakawa.

Ethics declarations

Conflict of interest

YM received a grant from The Ministry of Health, Labour and Welfare, Japan, and received personal fees from Zenyaku Kogyo Ltd. and Kainos Ltd. YF receives royalties for a patent for Assay kits for ADAMTS13 activity. MM received grants from The Ministry of Health, Labour and Welfare, Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Takeda Science Foundation, and received a grant and personal fees from Chugai Pharmaceutical. SO received a grant and personal fees from Chugai Pharmaceutical. All other authors declare that they have no conflict of interest.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miyakawa, Y., Imada, K., Ichinohe, T. et al. Efficacy and safety of rituximab in Japanese patients with acquired thrombotic thrombocytopenic purpura refractory to conventional therapy. Int J Hematol 104, 228–235 (2016). https://doi.org/10.1007/s12185-016-2019-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-016-2019-x

Keywords

Search

Navigation