Defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome following nontransplant-associated chemotherapy: Final results from a post hoc analysis of data from an expanded-access program

Nancy A. Kernan, Paul G. Richardson, Angela R. Smith, Brandon M. Triplett, Joseph H. Antin, Leslie Lehmann, Yoav Messinger, Wei Liang, Robin Hume, William Tappe, Robert J. Soiffer, Stephan A. Grupp

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10 Scopus citations

Abstract

Background: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant-associated chemotherapy. Following HSCT, VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Prior to US approval, defibrotide was available to treat VOD/SOS through an expanded-access treatment (T-IND) program. A post hoc analysis of nontransplant-associated VOD/SOS patients treated with defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented. Procedure: Patients were diagnosed by Baltimore or modified Seattle criteria or biopsy, and received defibrotide 25 mg/kg/day in four divided doses (≥21 days recommended). Results: Of the 1,154 patients in the T-IND, 137 had nontransplant-associated VOD/SOS, 82 of whom developed VOD/SOS within 30 days of starting chemotherapy. Of them, 66 (80.5%) were aged ≤16 years. Across all the 82 patients, Kaplan–Meier estimated day +70 survival was 74.1%, 65.8% in patients with MOD (n = 38), and 81.3% in patients without MOD (n = 44). By age group, Kaplan–Meier estimated day +70 survival was 80.1% in pediatric patients (n = 66) and 50.0% in adults (n = 16). Treatment-related adverse events occurred in 26.8%. Conclusions: In this post hoc analysis of 82 patients initiating defibrotide within 30 days of starting chemotherapy, Kaplan–Meier estimated survival was 74.1% at 70 days after defibrotide initiation. Safety profile was consistent with prior defibrotide studies.

Original languageEnglish (US)
Article numbere27269
JournalPediatric Blood and Cancer
Volume65
Issue number10
DOIs
StatePublished - Oct 2018

Bibliographical note

Funding Information:
Clinical research was funded by Jazz Pharmaceuticals. The authors thank Michael Feirtag and The Curry Rockefeller Group, LLC, of Tarrytown, NY, USA, for providing medical writing support and editorial support, which was funded by Jazz Pharmaceuticals in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

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. Paul G. Richardson has served on advisory committees and as a consultant, and received research funding from Jazz Pharmaceuticals. Angela R. Smith, Brandon M. Triplett, and Leslie Lehmann have no relevant conflicts of interest to disclose. Joseph H. Antin has served on advisory committees with Jazz Pharmaceuticals. Yoav Messinger has served on an advisory committee with Jazz Pharmaceuticals. Wei Liang was an employee of Jazz Pharmaceuticals and holds stock and/or stock options in Jazz Pharmaceuticals plc. 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. Stephan A. Grupp has served as a consultant to Jazz Pharmaceuticals.

Keywords

  • HSCT
  • VOD/SOS
  • defibrotide
  • nontransplant-associated chemotherapy

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