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Evaluation of the safety and efficacy of recombinant soluble thrombomodulin for patients with disseminated intravascular coagulation associated with acute leukemia: multicenter prospective study by the Tohoku Hematology Forum

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Abstract

It has been suggested that use of recombinant soluble thrombomodulin (rTM) is superior to conventional drugs in treatment of disseminated intravascular coagulation (DIC) complicating acute leukemia. However, its safety and efficacy have not been fully examined in prospective studies. Here, we performed a multicenter prospective study to examine outcomes of rTM treatment for DIC in patients with acute leukemia. Of 33 patients registered in this study, 13 had acute myeloid leukemia (AML), three had acute lymphoblastic leukemia (ALL), and 17 had acute promyelocytic leukemia (APL). The cumulative rates of DIC resolution at day 7 and day 35 were 56 and 81% in AML/ALL and 53 and 77% in APL, respectively. The median time from the initiation of rTM to DIC resolution was 4 days in AML/ALL and 6 days in APL patients. Adverse events related to hemorrhage occurred in two AML/ALL patients (13%) and three APL patients (18%). Of these, one AML/ALL patient died with intracranial hemorrhage, and two APL patients died with intracranial hemorrhage and pulmonary hemorrhage. These results suggest that rTM may improve the survival of acute leukemia patients with DIC by inhibiting early death related to hemorrhagic events, as reported previously.

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References

  1. Barbui T, Falanga A. Disseminated intravascular coagulation in acute leukemia. Semin Thromb Hemost. 2001;27:593–604.

    Article  CAS  PubMed  Google Scholar 

  2. Rickles FR, Falanga A, Montesinos P, Sanz MA, Brenner B, Barbui T. Bleeding and thrombosis in acute leukemia: what does the future of therapy look like? Thromb Res. 2007;120:S99–106.

    Article  PubMed  Google Scholar 

  3. Fenaux P. Management of acute promyelocytic leukemia. Eur J Haematol. 1993;50:65–73.

    Article  CAS  PubMed  Google Scholar 

  4. Rodeghiero F, Castaman G. The pathophysiology and treatment of hemorrhagic syndrome of acute promyelocytic leukemia. Leukemia. 1994;8(Suppl 2):S20–6.

    PubMed  Google Scholar 

  5. Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, et al. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell’Adulto and Associazione Italiana di Ematologia ed Oncologia Pe. Blood. 1997;90:1014–21.

  6. Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999;94:1192–200.

    CAS  PubMed  Google Scholar 

  7. Yanada M, Matsushita T, Asou N, Kishimoto Y, Tsuzuki M, Maeda Y, et al. Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome. Eur J Haematol. 2007;78:213–9.

    Article  PubMed  Google Scholar 

  8. Di Bona E, Avvisati G, Castaman G, Luce Vegna M, De Sanctis V, Rodeghiero F, et al. Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia. Br J Haematol. 2000;108:689–95.

    Article  PubMed  Google Scholar 

  9. Sanz MA, Martín G, Rayón C, Esteve J, González M, Díaz-Mediavilla J, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood. 1999;94:3015–21.

    CAS  PubMed  Google Scholar 

  10. Rodeghiero F, Avvisati G, Castaman G, Barbui T, Mandelli F. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. Blood. 1990;75:2112–7.

    CAS  PubMed  Google Scholar 

  11. Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 2011;118:1248–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McClellan JS, Kohrt HE, Coutre S, Gotlib JR, Majeti R, Alizadeh AA, et al. Treatment advances have not improved the early death rate in acute promyelocytic leukemia. Haematologica. 2012;97:133–6.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Sakuragawa N, Hasegawa H, Maki M, Nakagawa M, Nakashima M. Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC)—a multicenter co-operative double-blind trial in comparison with heparin. Thromb Res. 1993;72:475–500.

    Article  CAS  PubMed  Google Scholar 

  14. Ibbotson T, Perry CM. Danaparoid: a review of its use in thromboembolic and coagulation disorders. Drugs. 2002;62:2283–314.

    Article  CAS  PubMed  Google Scholar 

  15. Aoki N, Matsuda T, Saito H, Takatsuki K, Okajima K, Takahashi H, et al. A comparative double-blind randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation. Int J Hematol. 2002;75:540–7.

    Article  CAS  PubMed  Google Scholar 

  16. Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, et al. Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the recommendations from three guidelines. J Thromb Haemost. 2013;11:761–7.

    Article  CAS  Google Scholar 

  17. Nakashima M, Kanamaru M, Umemura K, Tsuruta K. Pharmacokinetics and safety of a novel recombinant soluble human thrombomodulin, ART-123, in healthy male volunteers. J Clin Pharmacol. 1998;38:40–4.

    Article  CAS  PubMed  Google Scholar 

  18. Maruyama I. Recombinant thrombomodulin and activated protein C in the treatment of disseminated intravascular coagulation. Thromb Haemost. 1999;82:718–21.

    CAS  PubMed  Google Scholar 

  19. Mohri M, Sugimoto E, Sata M, Asano T. The inhibitory effect of recombinant human soluble thrombomodulin on initiation and extension of coagulation—a comparison with other anticoagulants. Thromb Haemost. 1999;82:1687–93.

    CAS  PubMed  Google Scholar 

  20. Moll S, Lindley C, Pescatore S, Morrison D, Tsuruta K, Mohri M, et al. Phase I study of a novel recombinant human soluble thrombomodulin, ART-123. J Thromb Haemost. 2004;2:1745–51.

    Article  CAS  PubMed  Google Scholar 

  21. Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost. 2007;5:31–41.

    Article  CAS  PubMed  Google Scholar 

  22. Ikezoe T, Takeuchi A, Isaka M, Arakawa Y, Iwabu N, Kin T, et al. Recombinant human soluble thrombomodulin safely and effectively rescues acute promyelocytic leukemia patients from disseminated intravascular coagulation. Leuk Res. 2012;36:1398–402.

    Article  CAS  PubMed  Google Scholar 

  23. Kawano N, Kuriyama T, Yoshida S, Yamashita K, Ochiai H, Nakazaki S, et al. Clinical features and treatment outcomes of six patients with disseminated intravascular coagulation resulting from acute promyelocytic leukemia and treated with recombinant human soluble thrombomodulin at a single institution. Intern Med. 2013;52:55–62.

    Article  CAS  PubMed  Google Scholar 

  24. Kawano N, Tasaki A, Kuriyama T, Tahara Y, Yoshida S, Ono N, et al. Effects of recombinant human soluble thrombomodulin treatment for disseminated intravascular coagulation at a single institution–an analysis of 62 cases caused by infectious diseases and 30 cases caused by hematological diseases. Intern Med. 2014;53:205–13.

    Article  PubMed  Google Scholar 

  25. Asakura H, Takahashi H, Tsuji H, Matsushita T, Ninomiya H, Honda G, et al. Post-marketing surveillance of thrombomodulin alfa, a novel treatment of disseminated intravascular coagulation—safety and efficacy in 1,032 patients with hematologic malignancy. Thromb Res. 2014;133:364–70.

    Article  CAS  PubMed  Google Scholar 

  26. Matsushita T, Watanabe J, Honda G, Mimuro J, Takahashi H, Tsuji H, et al. Thrombomodulin alfa treatment in patients with acute promyelocytic leukemia and disseminated intravascular coagulation: a retrospective analysis of an open-label, multicenter, post-marketing surveillance study cohort. Thromb Res. 2014;133:772–81.

    Article  CAS  PubMed  Google Scholar 

  27. Takezako N, Sekiguchi N, Nagata A, Homma C, Takezako Y, Noto S, et al. Recombinant human thrombomodulin in the treatment of acute myeloid leukemia patients complicated by disseminated intravascular coagulation: retrospective analysis of outcomes between patients treated with heparin and recombinant human thrombomodulin thera. Thromb Res. 2015;136:20–3.

    Article  CAS  PubMed  Google Scholar 

  28. Kobayashi N, Maekawa T, Takada M, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan. Bibl Haematol. 1983;49:265–75.

    Google Scholar 

  29. Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  PubMed  Google Scholar 

  30. Creutzig U, Zimmermann M, Reinhardt D, Dworzak M, Stary J, Lehrnbecher T. Early deaths and treatment-related mortality in children undergoing therapy for acute myeloid leukemia: analysis of the multicenter clinical trials AML-BFM 93 and AML-BFM 98. J Clin Oncol. 2004;22:4384–93.

    Article  PubMed  Google Scholar 

  31. Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Möllgård L, et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia. 2011;25:1128–34.

    Article  CAS  PubMed  Google Scholar 

  32. Rahmé R, Thomas X, Recher C, Vey N, Delaunay J, Deconinck E, et al. Early death in acute promyelocytic leukemia (APL) in French centers: a multicenter study in 399 patients. Leukemia. 2014;28:2422–4.

    Article  PubMed  Google Scholar 

  33. Sletnes KE, Godal HC, Wisløff F. Disseminated intravascular coagulation (DIC) in adult patients with acute leukaemia. Eur J Haematol. 1995;54:34–8.

    Article  CAS  PubMed  Google Scholar 

  34. Abrahão R, Keogh RH, Lichtensztajn DY, Marcos-Gragera R, Medeiros BC, Coleman MP, et al. Predictors of early death and survival among children, adolescents and young adults with acute myeloid leukaemia in California, 1988–2011: a population-based study. Br J Haematol. 2016;173:292–302.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Uchiumi H, Matsushima T, Yamane A, Doki N, Irisawa H, Saitoh T, et al. Prevalence and clinical characteristics of acute myeloid leukemia associated with disseminated intravascular coagulation. Int J Hematol. 2007;86:137–42.

    Article  PubMed  Google Scholar 

  36. de la Serna J, Montesinos P, Vellenga E, Rayón C, Parody R, León A, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood. 2008;111:3395–402.

    Article  PubMed  Google Scholar 

  37. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113:1875–91.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank all of the physicians and staff of the Tohoku Hematology Forum for their contributions. This study was supported by NPO Tohoku Hematology Expert Meeting.

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Authors and Affiliations

  1. Department of Hematology, Sendai Medical Center, National Hospital Organization, 2-8-8, Miyagino, Miyagino-ku, Sendai, 983-8520, Japan

    Hisayuki Yokoyama, Yuna Katsuoka, Mitsue Inomata, Toshihiro Ito & Kuniaki Meguro

  2. Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan

    Naoto Takahashi & Yoshihiro Kameoka

  3. Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, Japan

    Riko Tsumanuma

  4. Department of Hematology, Iwate Prefectural Central Hospital, Morioka, Japan

    Kazunori Murai

  5. Department of Hematology, Fukushima Medical University, Fukushima, Japan

    Hideyoshi Noji

  6. Department of Hematology and Cell Therapy, Yamagata University Graduate School of Medicine, Yamagata, Japan

    Kenichi Ishizawa

  7. Department of Hematology/Oncology, Iwate Medical University School of Medicine, Morioka, Japan

    Shigeki Ito

  8. Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Yasushi Onishi & Hideo Harigae

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  1. Hisayuki Yokoyama
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Correspondence to Hisayuki Yokoyama.

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Yokoyama, H., Takahashi, N., Katsuoka, Y. et al. Evaluation of the safety and efficacy of recombinant soluble thrombomodulin for patients with disseminated intravascular coagulation associated with acute leukemia: multicenter prospective study by the Tohoku Hematology Forum. Int J Hematol 105, 606–613 (2017). https://doi.org/10.1007/s12185-017-2190-8

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  • DOI: https://doi.org/10.1007/s12185-017-2190-8

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