Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial

被引：302

作者：

Corbacioglu, Selim ^{[1
]}

Cesaro, Simone ^{[2
]}

Faraci, Maura ^{[3
]}

Valteau-Couanet, Dominique ^{[4
]}

Gruhn, Bernd ^{[5
]}

Rovelli, Attilio ^{[6
]}

Boelens, Jaap J. ^{[7
]}

Hewitt, Annette ^{[8
]}

Schrum, Johanna ^{[9
]}

Schulz, Ansgar S. ^{[10
]}

Mueller, Ingo ^{[11
]}

Stein, Jerry ^{[12
]}

Wynn, Robert ^{[13
]}

Greil, Johann ^{[14
]}

Sykora, Karl-Walter ^{[15
]}

Matthes-Martin, Susanne ^{[16
]}

Fuehrer, Monika ^{[17
]}

O'Meara, Anne ^{[18
]}

Toporski, Jacek ^{[19
]}

Sedlacek, Petr ^{[20
]}

Schlegel, Paul G. ^{[21
]}

Ehlert, Karoline ^{[22
]}

Fasth, Anders ^{[23
]}

Winiarski, Jacek ^{[24
]}

Arvidson, Johan ^{[25
]}

Mauz-Koerholz, Christine ^{[26
]}

Ozsahin, Hulya ^{[27
]}

Schrauder, Andre ^{[28
]}

Bader, Peter ^{[29
]}

Massaro, Joseph ^{[30
]}

D'Agostino, Ralph ^{[30
]}

Hoyle, Margaret ^{[31
]}

Iacobelli, Massimo ^{[31
]}

Debatin, Klaus-Michael ^{[10
]}

Peters, Christina ^{[16
]}

Dini, Giorgio ^{[3
]}

机构：

[1] Univ Regensburg, D-93053 Regensburg, Germany

[2] Univ Padua, Padua, Italy

[3] G Gaslini Inst Children, Genoa, Italy

[4] Inst Gustave Roussy, Villejuif, France

[5] Univ Hosp Jena, Jena, Germany

[6] Univ Milano Bicocca, Monza, Italy

[7] Univ Med Ctr, Utrecht, Netherlands

[8] Great Ormond St Hosp Sick Children, London, England

[9] Univ Hamburg Eppendorf, Hamburg, Germany

[10] Univ Childrens Hosp, Ulm, Germany

[11] Univ Childrens Hosp, Tubingen, Germany

[12] Schneider Childrens Med Ctr, Petah Tiqwa, Israel

[13] Royal Manchester Childrens Hosp, Manchester M27 1HA, Lancs, England

[14] Univ Childrens Hosp, Heidelberg, Germany

[15] Hannover Med Sch, Hannover, Germany

[16] St Anna Childrens Hosp, A-1090 Vienna, Austria

[17] Univ Childrens Hosp, Munich, Germany

[18] Our Ladys Childrens Hosp, Dublin, Ireland

[19] Skane Univ Hosp, Lund, Sweden

[20] Univ Hosp Motol, Prague, Czech Republic

[21] Univ Childrens Hosp, Wurzburg, Germany

[22] Univ Childrens Hosp, Munster, Germany

[23] Univ Gothenburg, Dept Pediat, Gothenburg, Sweden

[24] Karolinska Inst, Stockholm, Sweden

[25] Uppsala Univ, Childrens Hosp, Uppsala, Sweden

[26] Univ Halle Wittenberg, Halle, Germany

[27] Univ Childrens Hosp, Geneva, Switzerland

[28] Univ Hosp Schleswig Holstein, Kiel, Germany

[29] Univ Childrens Hosp, Frankfurt, Germany

[30] Boston Univ, Boston, MA 02215 USA

[31] Gentium SpA, Villa Guardia, Como, Italy

来源：

LANCET | 2012年 / 379卷 / 9823期

关键词：

BONE-MARROW-TRANSPLANTATION; COMPETING RISKS; CHILDREN; LIVER; DIAGNOSIS; COHORT; BLOOD; PREVENTION; RECIPIENTS; BUSULFAN;

D O I：

10.1016/S0140-6736(11)61938-7

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Background Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting. Methods In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1: 1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948. Findings Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7.7%, 95% CI -15.3 to -0.1; Z test for competing risk analysis p=0.0488; log-rank test p=0.0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls. Interpretation Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT.

引用

页码：1301 / 1309

页数：9

共 39 条

[1]

AALEN OO, 1978, SCAND J STAT, V5, P141

[2]

Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients [J].