Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome

Nancy A. Kernan, Stephan Grupp, Angela R. Smith, Sally Arai, Brandon Triplett, Joseph H. Antin, Leslie Lehmann, Tsiporah Shore, Vincent T. Ho, Nancy Bunin, Massimo Iacobelli, Wei Liang, Robin Hume, William Tappe, Robert Soiffer, Paul Richardson

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92 Scopus citations

Abstract

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi-organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded-access treatment programme (T-IND; NCT00628498). In the completed T-IND, the Kaplan–Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7–61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8–71·6%) and 47·1% (95% CI, 42·3–51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier defibrotide initiation was also associated with higher Day +100 survival. The safety profile of defibrotide in the completed T-IND study was similar to previous reports.

Original languageEnglish (US)
Pages (from-to)816-827
Number of pages12
JournalBritish journal of haematology
Volume181
Issue number6
DOIs
StatePublished - Jun 2018

Bibliographical note

Funding Information:
Nancy A. Kernan received grants from Gentium during the conduct of the study, and her research was supported by National Cancer Institute of the National Institutes of Health under award number P30 CA008748; the content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. Stephan A. Grupp has served as a consultant to Jazz Pharmaceuticals. Angela R. Smith, Sally Arai, Brandon M. Triplett, Leslie Leh-mann, Tsiporah Shore, and Nancy Bunin have no relevant conflicts of interest to disclose. Joseph H. Antin has served on advisory committees with Jazz Pharmaceuticals. Vincent T. Ho has served as a consultant to Jazz Pharmaceuticals. Massimo Iacobelli was an employee of Gentium SpA during the conduct of the study. Wei Liang, Robin Hume, and William Tappe are employees of Jazz Pharmaceuticals and hold stock and/or stock options in Jazz Pharmaceuticals plc. Robert J. Soiffer has served on advisory committees with Jazz Pharmaceuticals. Paul G. Richardson has served on advisory committees and as a consultant, and received research funding from Jazz Pharmaceuticals.

Funding Information:
Clinical research was funded by Jazz Pharmaceuticals. The authors thank Katherine Molnar-Kimber, PhD, and John Norwood of The Curry Rockefeller Group, LLC, of Tarry-town, NY, USA, for providing medical writing and editorial support, which were funded by Jazz Pharmaceuticals in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Jazz Pharmaceuticals also reviewed and edited the manuscript for scientific accuracy. The authors would like to thank all of the study investigators, study staff, nursing team, and patients for their participation in this research.

Publisher Copyright:
© 2018 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

Keywords

  • defibrotide
  • haematopoietic stem cell transplant
  • multi-organ dysfunction
  • sinusoidal obstruction syndrome
  • veno-occlusive disease

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