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.

  • Article
  • Published:

A multicentre, multinational, prospective, observational registry study of defibrotide in patients diagnosed with veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation: an EBMT study

Bone Marrow Transplantation volume 56, pages 2454–2463 (2021)Cite this article

Subjects

Abstract

Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT). This multinational, prospective, observational study (NCT03032016), performed by the EBMT, enrolled patients treated with defibrotide from April 2015 to July 2018. This analysis focused on defibrotide-treated patients with VOD/SOS post-HCT. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were enrolled: 62 had severe VOD/SOS and comprised the primary study population, including 36 with multi-organ dysfunction/failure (MOD/MOF). SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan–Meier–estimated Day 100 survival rate was 73% (95% CI: 60%, 82%) with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. MOD/MOF resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis. Results from this multicentre registry study build on prior defibrotide studies supporting the utility of defibrotide for the treatment of VOD/SOS post-HCT. These results provide additional real-world evidence of the effectiveness and safety of defibrotide in patients with VOD/SOS post-HCT.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Flow diagram of patients enrolled in the EBMT PASS.
Fig. 2: Kaplan–Meier–estimated survival by severity of VOD/SOS.
Fig. 3: Kaplan–Meier–estimated survival by severity of VOD/SOS and age.

Similar content being viewed by others

Data availability

All relevant data are provided within the paper and supporting files.

References

  1. Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transpl. 2010;16:157–68.

    Article  Google Scholar 

  2. Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transpl. 2018;53:138–45.

    Article  CAS  Google Scholar 

  3. Dalle JH, Giralt SA. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment. Biol Blood Marrow Transpl. 2016;22:400–9.

    Article  Google Scholar 

  4. Richardson PG, Corbacioglu S, Ho VT, Kernan NA, Lehmann L, Maguire C, et al. Drug safety evaluation of defibrotide. Expert Opin Drug Saf. 2013;12:123–36.

    Article  CAS  Google Scholar 

  5. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85:3005–20.

    Article  CAS  Google Scholar 

  6. Fan CQ, Crawford JM. Sinusoidal obstruction syndrome (hepatic veno-occlusive disease). J Clin Exp Hepatol. 2014;4:332–46.

    Article  Google Scholar 

  7. Carreras E, Diaz-Ricart M. Early complications of endothelial origin. In: Carreras E, Dufour C, Mohty M, Kroger N, editors. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. Cham (CH): Springer; 2019. p. 315–22.

  8. Richardson PG, Triplett BM, Ho VT, Chao N, Dignan FL, Maglio M, et al. Defibrotide sodium for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Expert Rev Clin Pharm. 2018;11:113–24.

    Article  CAS  Google Scholar 

  9. Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Br J Haematol. 2015;168:481–91.

    Article  Google Scholar 

  10. Defitelio® (defibrotide sodium) injection, for intravenous use [packet insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2016. https://pp.jazzpharma.com/pi/defitelio.en.USPI.pdf.

  11. Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127:1656–65.

    Article  CAS  Google Scholar 

  12. Kernan NA, Grupp S, Smith AR, Arai S, Triplett B, Antin JH, et al. Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Br J Haematol. 2018;181:816–27.

    Article  CAS  Google Scholar 

  13. Corbacioglu S, Carreras E, Mohty M, Pagliuca A, Boelens JJ, Damaj G, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: final results from the International Compassionate-use Program. Biol Blood Marrow Transpl. 2016;22:1874–82.

    Article  CAS  Google Scholar 

  14. Defitelio® (defibrotide sodium) [summary of product characteristics]. Villa Guardia, Italy: Gentium SpA; 2018. https://www.ema.europa.eu/en/documents/product-information/defitelio-epar-product-information_en.pdf.

  15. Mohty M, Labopin M, Lebon D, Berceanu A, Jubert C, Yakoub-Agha I, et al. Efficacy and safety of defibrotide in the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following haematopoietic stem cell transplantation: interim results from the DEFIFrance study. Poster presented at: 45th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT); 24–27 March 2019; Frankfurt, Germany.

  16. Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, et al. Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transpl. 2016;51:906–12.

    Article  CAS  Google Scholar 

  17. Mohty M, Malard F, Abecasis M, Aerts E, Alaskar AS, Aljurf M, et al. Prophylactic, preemptive, and curative treatment for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a position statement from an international expert group. Bone Marrow Transpl. 2019;55:485–95.

    Article  Google Scholar 

  18. Corbacioglu S, Jabbour EJ, Mohty M. Risk factors for development of and progression of hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Biol Blood Marrow Transpl. 2019;25:1271–80.

    Article  Google Scholar 

  19. Beelen DW, Trenschel R, Stelljes M, Groth C, Masszi T, Remenyi P, et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet Haematol. 2020;7:e28–e39.

    Article  Google Scholar 

  20. Danylesko I, Shimoni A, Nagler A. Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. Bone Marrow Transpl. 2012;47:5–14.

    Article  CAS  Google Scholar 

  21. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255–67.

    Article  CAS  Google Scholar 

  22. Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44:778–83.

    Article  CAS  Google Scholar 

  23. Bearman SI, Anderson GL, Mori M, Hinds MS, Shulman HM, McDonald GB. Venoocclusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation. J Clin Oncol. 1993;11:1729–36.

    Article  CAS  Google Scholar 

  24. Cairo MS, Cooke KR, Lazarus HM, Chao N. Modified diagnostic criteria, grading classification and newly elucidated pathophysiology of hepatic SOS/VOD after haematopoietic cell transplantation. Br J Haematol. 2020;190:822–36.

Download references

Acknowledgements

This study was supported by Jazz Pharmaceuticals. Medical writing and editorial assistance were provided by Erica Chevalier-Larsen, PhD, CMPP™, of SciFluent Communications, Inc., and were financially supported by Jazz Pharmaceuticals.

Author information

Authors and Affiliations

  1. Department of Clinical Haematology and Cellular Therapy, Hôpital St Antoine, Sorbonne University, INSERM UMRs 938, Paris, France

    Mohamad Mohty

  2. Hematology Clinic, University of Udine, Udine, Italy

    Marta Lisa Battista

  3. Institut Paoli Calmettes, Aix-Marseille University, CNRS, INSERM, CRCM, Marseille, France

    Didier Blaise

  4. Department of Pediatric Hematology-Oncology, Azienda Ospedale, Università di Padova, Padova, Italy

    Elisabetta Calore

  5. Pediatric Hematology-Oncology, Department of Mother and Child Health, Azienda Ospedaliera Universitaria Integrata, Verona, Italy

    Simone Cesaro

  6. Bone Marrow Transplant Unit, Institute for Maternal and Child Health – IRCCS Burlo Garofolo, Trieste, Italy

    Natalia Maximova

  7. Mother and Child Health, Santa Maria della Misericordia Hospital, Perugia, Italy

    Katia Perruccio

  8. Pediatric Hematology, Instutu d’Hématologie et d’Oncologie Pédiatrique, Lyon, France

    Cecile Renard

  9. Department of Blood and Marrow Transplant, Royal Manchester Children’s Hospital, Manchester, UK

    Robert Wynn

  10. Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

    Marco Zecca

  11. Department of Haematology and EBMT Paris study office/CEREST-TC, Hôpital St Antoine, INSERM UMR 938 and Université Pierre et Marie Curie, Paris, France

    Myriam Labopin

  12. Research and Development, Jazz Pharmaceuticals, Oxford, UK

    Raj Hanvesakul

  13. Clinical Development, Jazz Pharmaceuticals, Oxford, UK

    Vian Amber

  14. Biostatistics, Jazz Pharmaceuticals, Philadelphia, PA, USA

    Robert J. Ryan

  15. Department of Haematology, Birmingham Children’s Hospital, Birmingham, UK

    Sarah Lawson

  16. Department of Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Fabio Ciceri

Authors
  1. Mohamad Mohty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marta Lisa Battista
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Didier Blaise
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elisabetta Calore
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Simone Cesaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Natalia Maximova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katia Perruccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cecile Renard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Robert Wynn
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marco Zecca
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Myriam Labopin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Raj Hanvesakul
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Vian Amber
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Robert J. Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Sarah Lawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Fabio Ciceri
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MM, ML, and RJR designed the research study. MLB, DB, EC, SC, NM, KP, CR, RW, MZ, and SL performed the research. MM, NM, ML, RJ, VA, and RJR analysed the data. FC contributed essential reagents or tools. All authors wrote and critically revised the paper.

Corresponding author

Correspondence to Mohamad Mohty.

Ethics declarations

Conflict of interest

MM has received honoraria and research funding from Jazz Pharmaceuticals. DB and ML have received honoraria from Jazz Pharmaceuticals. RH, VA, and RJR are employees of and hold stock ownership and/or stock options in Jazz Pharmaceuticals. SL has received a consultancy honorarium from Jazz Pharmaceuticals. MLB, EC, SC, NM, KP, CR, RW, MZ and FC have no competing interests to disclose.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mohty, M., Battista, M.L., Blaise, D. et al. A multicentre, multinational, prospective, observational registry study of defibrotide in patients diagnosed with veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation: an EBMT study. Bone Marrow Transplant 56, 2454–2463 (2021). https://doi.org/10.1038/s41409-021-01265-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-021-01265-2

This article is cited by

Search

Advanced search

Quick links