Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure

Paul G. Richardson, Marcie L. Riches, Nancy A. Kernan, Joel A. Brochstein, Shin Mineishi, Amanda M. Termuhlen, Sally Arai, Stephan A. Grupp, Eva C. Guinan, Paul L. Martin, Gideon Steinbach, Amrita Krishnan, Eneida Nemecek, Sergio Giralt, Tulio Rodriguez, Reggie Duerst, John Doyle, Joseph H. Antin, Angela Smith, Leslie LehmannRichard Champlin, Alfred Gillio, Rajinder Bajwa, Ralph B. D'Agostino, Joseph Massaro, Diane Warren, Maja Miloslavsky, Robin L. Hume, Massimo Iacobelli, Bijan Nejadnik, Alison L. Hannah, Robert J. Soiffer

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS withmulti-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day 1100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8; P =.0109, using a propensityadjusted analysis). Observed day 1100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6; P =.0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8%and 9.4%])was similar between the defibrotide and control groups, respectively.Defibrotide was associated with significant improvement in day 1100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00358501.

Original languageEnglish (US)
Pages (from-to)1656-1665
Number of pages10
JournalBlood
Volume127
Issue number13
DOIs
StatePublished - Mar 31 2016

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Hepatic Veno-Occlusive Disease
Hematopoietic Stem Cell Transplantation
Stem cells
Therapeutics
Confidence Intervals
Hemorrhage
Survival
Mortality
defibrotide
Rare Diseases
Hypotension
Toxicity
Safety
Lung
Control Groups

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Medicine(all)
  • Hematology
  • Cell Biology

Cite this

Richardson, P. G., Riches, M. L., Kernan, N. A., Brochstein, J. A., Mineishi, S., Termuhlen, A. M., ... Soiffer, R. J. (2016). Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood, 127(13), 1656-1665. https://doi.org/10.1182/blood-2015-10-676924

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. / Richardson, Paul G.; Riches, Marcie L.; Kernan, Nancy A.; Brochstein, Joel A.; Mineishi, Shin; Termuhlen, Amanda M.; Arai, Sally; Grupp, Stephan A.; Guinan, Eva C.; Martin, Paul L.; Steinbach, Gideon; Krishnan, Amrita; Nemecek, Eneida; Giralt, Sergio; Rodriguez, Tulio; Duerst, Reggie; Doyle, John; Antin, Joseph H.; Smith, Angela; Lehmann, Leslie; Champlin, Richard; Gillio, Alfred; Bajwa, Rajinder; D'Agostino, Ralph B.; Massaro, Joseph; Warren, Diane; Miloslavsky, Maja; Hume, Robin L.; Iacobelli, Massimo; Nejadnik, Bijan; Hannah, Alison L.; Soiffer, Robert J.

In: Blood, Vol. 127, No. 13, 31.03.2016, p. 1656-1665.

Research output: Contribution to journalArticle

Richardson, PG, Riches, ML, Kernan, NA, Brochstein, JA, Mineishi, S, Termuhlen, AM, Arai, S, Grupp, SA, Guinan, EC, Martin, PL, Steinbach, G, Krishnan, A, Nemecek, E, Giralt, S, Rodriguez, T, Duerst, R, Doyle, J, Antin, JH, Smith, A, Lehmann, L, Champlin, R, Gillio, A, Bajwa, R, D'Agostino, RB, Massaro, J, Warren, D, Miloslavsky, M, Hume, RL, Iacobelli, M, Nejadnik, B, Hannah, AL & Soiffer, RJ 2016, 'Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure', Blood, vol. 127, no. 13, pp. 1656-1665. https://doi.org/10.1182/blood-2015-10-676924
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 Mar 31;127(13):1656-1665. https://doi.org/10.1182/blood-2015-10-676924
Richardson, Paul G. ; Riches, Marcie L. ; Kernan, Nancy A. ; Brochstein, Joel A. ; Mineishi, Shin ; Termuhlen, Amanda M. ; Arai, Sally ; Grupp, Stephan A. ; Guinan, Eva C. ; Martin, Paul L. ; Steinbach, Gideon ; Krishnan, Amrita ; Nemecek, Eneida ; Giralt, Sergio ; Rodriguez, Tulio ; Duerst, Reggie ; Doyle, John ; Antin, Joseph H. ; Smith, Angela ; Lehmann, Leslie ; Champlin, Richard ; Gillio, Alfred ; Bajwa, Rajinder ; D'Agostino, Ralph B. ; Massaro, Joseph ; Warren, Diane ; Miloslavsky, Maja ; Hume, Robin L. ; Iacobelli, Massimo ; Nejadnik, Bijan ; Hannah, Alison L. ; Soiffer, Robert J. / Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. In: Blood. 2016 ; Vol. 127, No. 13. pp. 1656-1665.
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abstract = "Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS withmulti-organ failure (MOF) is associated with >80{\%} mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day 1100 post-HSCT; observed rates equaled 38.2{\%} in the defibrotide group and 25{\%} in the controls (23{\%} estimated difference; 95.1{\%} confidence interval [CI], 5.2-40.8; P =.0109, using a propensityadjusted analysis). Observed day 1100 complete response (CR) rates equaled 25.5{\%} for defibrotide and 12.5{\%} for controls (19{\%} difference using similar methodology; 95.1{\%} CI, 3.5-34.6; P =.0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8{\%} and 15.6{\%}] and gastrointestinal bleeding [7.8{\%}and 9.4{\%}])was similar between the defibrotide and control groups, respectively.Defibrotide was associated with significant improvement in day 1100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00358501.",
author = "Richardson, {Paul G.} and Riches, {Marcie L.} and Kernan, {Nancy A.} and Brochstein, {Joel A.} and Shin Mineishi and Termuhlen, {Amanda M.} and Sally Arai and Grupp, {Stephan A.} and Guinan, {Eva C.} and Martin, {Paul L.} and Gideon Steinbach and Amrita Krishnan and Eneida Nemecek and Sergio Giralt and Tulio Rodriguez and Reggie Duerst and John Doyle and Antin, {Joseph H.} and Angela Smith and Leslie Lehmann and Richard Champlin and Alfred Gillio and Rajinder Bajwa and D'Agostino, {Ralph B.} and Joseph Massaro and Diane Warren and Maja Miloslavsky and Hume, {Robin L.} and Massimo Iacobelli and Bijan Nejadnik and Hannah, {Alison L.} and Soiffer, {Robert J.}",
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T1 - Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure

AU - Richardson, Paul G.

AU - Riches, Marcie L.

AU - Kernan, Nancy A.

AU - Brochstein, Joel A.

AU - Mineishi, Shin

AU - Termuhlen, Amanda M.

AU - Arai, Sally

AU - Grupp, Stephan A.

AU - Guinan, Eva C.

AU - Martin, Paul L.

AU - Steinbach, Gideon

AU - Krishnan, Amrita

AU - Nemecek, Eneida

AU - Giralt, Sergio

AU - Rodriguez, Tulio

AU - Duerst, Reggie

AU - Doyle, John

AU - Antin, Joseph H.

AU - Smith, Angela

AU - Lehmann, Leslie

AU - Champlin, Richard

AU - Gillio, Alfred

AU - Bajwa, Rajinder

AU - D'Agostino, Ralph B.

AU - Massaro, Joseph

AU - Warren, Diane

AU - Miloslavsky, Maja

AU - Hume, Robin L.

AU - Iacobelli, Massimo

AU - Nejadnik, Bijan

AU - Hannah, Alison L.

AU - Soiffer, Robert J.

PY - 2016/3/31

Y1 - 2016/3/31

N2 - Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS withmulti-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day 1100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8; P =.0109, using a propensityadjusted analysis). Observed day 1100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6; P =.0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8%and 9.4%])was similar between the defibrotide and control groups, respectively.Defibrotide was associated with significant improvement in day 1100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00358501.

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