Download PDF
Semin Thromb Hemost 2019; 45(08): 767-777
DOI: 10.1055/s-0039-1698763
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Efficacy and Safety of Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Liping Yang‡   *
1   Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
3   Key Laboratory of Thrombosis and Haemostasis of the Ministry of Health, Soochow University, Suzhou, China
4   Collaborative Innovation Centre of Haematology, Soochow University, Suzhou, China
5   Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
,
Jiaqian Qi‡   *
1   Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
3   Key Laboratory of Thrombosis and Haemostasis of the Ministry of Health, Soochow University, Suzhou, China
4   Collaborative Innovation Centre of Haematology, Soochow University, Suzhou, China
5   Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
,
Tingting Pan
1   Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
3   Key Laboratory of Thrombosis and Haemostasis of the Ministry of Health, Soochow University, Suzhou, China
4   Collaborative Innovation Centre of Haematology, Soochow University, Suzhou, China
5   Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
,
Tao You
1   Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
3   Key Laboratory of Thrombosis and Haemostasis of the Ministry of Health, Soochow University, Suzhou, China
4   Collaborative Innovation Centre of Haematology, Soochow University, Suzhou, China
,
Changgeng Ruan
1   Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
2   State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
3   Key Laboratory of Thrombosis and Haemostasis of the Ministry of Health, Soochow University, Suzhou, China
4   Collaborative Innovation Centre of Haematology, Soochow University, Suzhou, China
,
Yue Han
1   Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
2   State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
3   Key Laboratory of Thrombosis and Haemostasis of the Ministry of Health, Soochow University, Suzhou, China
4   Collaborative Innovation Centre of Haematology, Soochow University, Suzhou, China
5   Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China
› Author Affiliations
Further Information

Publication History

Publication Date:
18 October 2019 (online)

    Permissions and Reprints

Abstract

Defibrotide has been approved in several geographic jurisdictions for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) for years. However, available data on efficacy and safety for its use in VOD are contrasting. We performed a meta-analysis to evaluate the efficacy and safety of defibrotide in the treatment of hepatic VOD/SOS post-hematopoietic stem cell transplantation (HSCT). PubMed and Embase were searched for studies regarding the efficacy and safety of defibrotide in VOD patients. Survival rate at day + 100 post-HSCT (D + 100 SR), as well as the prognosis, comprising complete response (CR), adverse events including ≥1 adverse event (≥1 AE), hemorrhage, and serious adverse events (SAEs), were pooled using a random effect model. Sixteen studies involving 3,002 participants were included. Pooled estimates for overall D + 100 SR as well as rate of CR, ≥1 AE, hemorrhage, SAEs in VOD patients post-HSCT were 58% (95% CI: 54–62%), 57% (95% CI: 45–68%), 65% (95% CI: 54–75%), 16% (95% CI: 5–27%), 53% (95% CI: 51–55%), respectively, and were 44% (95% CI: 39–48%), 39% (95% CI: 28–50%), 88% (95% CI: 71–100%), 42% (95% CI: 30–55%), 58% (95% CI: 52–64%), respectively, in severe VOD (sVOD) patients. Hemorrhage and hypotension were the most common AEs. Current evidence suggests that defibrotide improves the D + 100 SR and CR in VOD/sVOD patients following HSCT. However, the results of this review/meta-analysis were mainly based on data from observational studies, potentially subject to selection bias. Consequently, higher quality randomized control trials and larger prospective cohort studies are warranted.

Keywords

hepatic veno-occlusive disease - sinusoidal obstruction syndrome - defibrotide - hematopoietic stem cell transplantation.

* Liping Yang and Jiaqian Qi contributed equally to this study.


Supplementary Material

 

  • References

  • 1 Coppell JA, Richardson PG, Soiffer R. , et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant 2010; 16 (02) 157-168
    CrossrefPubMedGoogle Scholar
  • 2 Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 1995; 85 (11) 3005-3020
    CrossrefPubMedGoogle Scholar
  • 3 DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis 2002; 22 (01) 27-42
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Fan CQ, Crawford JM. Sinusoidal obstruction syndrome (hepatic veno-occlusive disease). J Clin Exp Hepatol 2014; 4 (04) 332-346
    CrossrefPubMedGoogle Scholar
  • 5 Tsirigotis PD, Resnick IB, Avni B. , et al. Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen. Bone Marrow Transplant 2014; 49 (11) 1389-1392
    CrossrefPubMedGoogle Scholar
  • 6 Jones RJ, Lee KS, Beschorner WE. , et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987; 44 (06) 778-783
    CrossrefPubMedGoogle Scholar
  • 7 McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Veno-occlusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 1984; 4 (01) 116-122
    CrossrefPubMedGoogle Scholar
  • 8 Shulman HM, Hinterberger W. Hepatic veno-occlusive disease—liver toxicity syndrome after bone marrow transplantation. Bone Marrow Transplant 1992; 10 (03) 197-214
    PubMedGoogle Scholar
  • 9 Bearman SI, Anderson GL, Mori M, Hinds MS, Shulman HM, McDonald GB. Veno-occlusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation. J Clin Oncol 1993; 11 (09) 1729-1736
    CrossrefPubMedGoogle Scholar
  • 10 Stein C, Castanotto D, Krishnan A, Nikolaenko L. Defibrotide (Defitelio): a new addition to the stockpile of food and drug administration-approved oligonucleotide drugs. Mol Ther Nucleic Acids 2016; 5: e346
    CrossrefPubMedGoogle Scholar
  • 11 Thiemermann C, Thomas GR, Vane JR. Defibrotide reduces infarct size in a rabbit model of experimental myocardial ischaemia and reperfusion. Br J Pharmacol 1989; 97 (02) 401-408
    CrossrefPubMedGoogle Scholar
  • 12 Carmona A, Díaz-Ricart M, Palomo M. , et al. Distinct deleterious effects of cyclosporine and tacrolimus and combined tacrolimus-sirolimus on endothelial cells: protective effect of defibrotide. Biol Blood Marrow Transplant 2013; 19 (10) 1439-1445
    CrossrefPubMedGoogle Scholar
  • 13 Palmer KJ, Goa KL. Defibrotide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in vascular disorders. Drugs 1993; 45 (02) 259-294
    PubMedGoogle Scholar
  • 14 Palomo M, Diaz-Ricart M, Rovira M, Escolar G, Carreras E. Defibrotide prevents the activation of macrovascular and microvascular endothelia caused by soluble factors released to blood by autologous hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011; 17 (04) 497-506
    CrossrefPubMedGoogle Scholar
  • 15 Pescador R, Capuzzi L, Mantovani M, Fulgenzi A, Ferrero ME. Defibrotide: properties and clinical use of an old/new drug. Vascul Pharmacol 2013; 59 (1-2): 1-10
    CrossrefPubMedGoogle Scholar
  • 16 Richardson PG, Elias AD, Krishnan A. , et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood 1998; 92 (03) 737-744
    PubMedGoogle Scholar
  • 17 Richardson PG, Soiffer RJ, Antin JH. , et al. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant 2010; 16 (07) 1005-1017
    CrossrefPubMedGoogle Scholar
  • 18 Moher D, Liberati A, Tetzlaff J, Altman DG. ; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009; 151 (04) 264-269 , W64
    PubMedGoogle Scholar
  • 19 Wells GA, Shea B, O'Connell D. , et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta–analysis. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp . Accessed December 12, 2018
    PubMedGoogle Scholar
  • 20 Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50 (04) 1088-1101
    CrossrefPubMedGoogle Scholar
  • 21 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315 (7109): 629-634
    CrossrefPubMedGoogle Scholar
  • 22 Abecasis M, Schuh J, Coelho I. , et al. Hepatic sinusoidal obstruction syndrome (SOS) following hematopoietic stem cell transplantation (HSCT): incidence, treatment and outcome in a cohort of 1,540 patients. Bone Marrow Transplant 2016; 51: S415-S416
    PubMedGoogle Scholar
  • 23 Baladé Martínez L, Cabezuelo MM, Villamañan Bueno E. , et al. Defibrotide for the treatment of severe hepatic sinusoidal obstruction syndrome: a single-centre experience. Eur J Hosp Pharm Sci Pract 2018 . Doi: 10.1136/ejhpharm-2018-001575 [epub ahead of print]
    PubMedGoogle Scholar
  • 24 Chopra R, Eaton JD, Grassi A. , et al. Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study. Br J Haematol 2000; 111 (04) 1122-1129
    CrossrefPubMedGoogle Scholar
  • 25 Corbacioglu S, Carreras E, Mohty M. , et al. Defibrotide for the treatment of hepatic veno-occlusive disease: final results from the international compassionate-use program. Biol Blood Marrow Transplant 2016; 22 (10) 1874-1882
    CrossrefPubMedGoogle Scholar
  • 26 Corbacioglu S, Greil J, Peters C. , et al. Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplant 2004; 33 (02) 189-195
    CrossrefPubMedGoogle Scholar
  • 27 Coutsouvelis J, Avery S, Dooley M, Kirkpatrick C, Spencer A. Defibrotide for the treatment of sinusoidal obstruction syndrome: evaluation of response to therapy and patient outcomes. Support Care Cancer 2018; 26 (03) 947-955
    CrossrefPubMedGoogle Scholar
  • 28 Kernan NA, Grupp S, Smith AR. , 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 (06) 816-827
    CrossrefPubMedGoogle Scholar
  • 29 Locatelli F, Faraci M, Cesaro S. , et al. Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following hematopoietic stem cell transplantation or chemotherapy-results from the Italian therapeutic use protocol. Blood 2015; 126 (23) 3107
    CrossrefPubMedGoogle Scholar
  • 30 Pol RR, Russell N, Das-Gupta E, Watson L, Rachael L, Byrne J. Incidence and management of hepatic severe veno-occlusive disease in 273 patients in a single centre with defibrotide. Bone Marrow Transplant 2016; 51 (09) 1262-1264
    CrossrefPubMedGoogle Scholar
  • 31 Richardson PG, Murakami C, Jin Z. , et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 2002; 100 (13) 4337-4343
    CrossrefPubMedGoogle Scholar
  • 32 Richardson PG, Riches ML, Kernan NA. , et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood 2016; 127 (13) 1656-1665
    CrossrefPubMedGoogle Scholar
  • 33 Richardson PG, Smith AR, Triplett BM. , et al; Defibrotide Study Group. Defibrotide for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome: interim results from a treatment IND study. Biol Blood Marrow Transplant 2017; 23 (06) 997-1004
    CrossrefPubMedGoogle Scholar
  • 34 Ruiz Ramos J, Company Albir MJ, Favieres Puigcerver C. , et al. Defibrotide for sinusoidal obstruction syndrome: a single centre experience. Eur J Hosp Pharm Sci Pract 2014; 21: A52
    PubMedGoogle Scholar
  • 35 Strouse C, Richardson P, Prentice G. , et al. Defibrotide for treatment of severe veno-occlusive disease in pediatrics and adults: an exploratory analysis using data from the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2016; 22 (07) 1306-1312
    CrossrefPubMedGoogle Scholar
  • 36 Yakushijin K, Ikezoe T, Ohwada C. , et al. Clinical effects of recombinant thrombomodulin and defibrotide on sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2019; 54 (05) 674-680
    CrossrefPubMedGoogle Scholar
  • 37 Bearman SI, Lee JL, Barón AE, McDonald GB. Treatment of hepatic veno-occlusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood 1997; 89 (05) 1501-1506
    CrossrefPubMedGoogle Scholar
  • 38 Richardson P, Aggarwal S, Topaloglu O. , et al. Systematic review of defibrotide studies in the treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS). Bone Marrow Transplant 2019 . Doi: 10.1038/s41409-019-0474-8. [epub ahead of print]
    PubMedGoogle Scholar
  • 39 Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Br J Haematol 2015; 168 (04) 481-491
    CrossrefPubMedGoogle Scholar
  • 40 Dignan FL, Wynn RF, Hadzic N. , et al; Haemato-oncology Task Force of British Committee for Standards in Haematology; British Society for Blood and Marrow Transplantation. BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol 2013; 163 (04) 444-457
    CrossrefPubMedGoogle Scholar
  • 41 Mohty M, Malard F, Abecassis M. , et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 2015; 50 (06) 781-789
    CrossrefPubMedGoogle Scholar
  • 42 Richardson PG, Ho VT, Cutler C, Glotzbecker B, Antin JH, Soiffer R. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: novel insights to pathogenesis, current status of treatment, and future directions. Biol Blood Marrow Transplant 2013; 19 (1, Suppl): S88-S90
    CrossrefPubMedGoogle Scholar