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, 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

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.

Keywords: defibrotide; haematopoietic stem cell transplant; multi-organ dysfunction; sinusoidal obstruction syndrome; veno-occlusive disease.

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

Figures

Figure 1
Figure 1
Kaplan–Meier estimated survival to Day +100 by MOD status (panel A) and age and MOD‐status subgroup (panel B), HSCT population. HSCT, haematopoietic stem cell transplant; MOD, multi‐organ dysfunction; VOD/SOS, veno‐occlusive disease/sinusoidal obstruction syndrome.
Figure 2
Figure 2
Timing of initiation of defibrotide after VOD/SOS diagnosis. MOD, multi‐organ dysfunction; VOD/SOS, veno‐occlusive disease/sinusoidal obstruction syndrome.
Figure 3
Figure 3
Kaplan–Meier estimated Day +100 survival by transplant type. HSCT, haematopoietic stem cell transplant; MOD, multi‐organ dysfunction.
Figure 4
Figure 4
Comparison of Kaplan–Meier estimated Day +100 survival by time of VOD/SOS onset post‐HSCT. HSCT, haematopoietic stem cell transplant; MOD, multi‐organ dysfunction; VOD/SOS, veno‐occlusive disease/sinusoidal obstruction syndrome.

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