Granulocyte-colony stimulating factor (G-CSF) to treat acute-on- chronic liver failure: A multicenter randomized trial (GRAFT study)

JOURNAL OF HEPATOLOGY

卷:75

Article

Engelmann, Cornelius^1,2,3  Herber, Adam¹  Franke, Annegret⁴  Bruns, Tony^5,6  Reuken, Philipp⁶  Schiefke, Ingolf⁷  Zipprich, Alexander⁸  Zeuzem, Stefan⁹  Goeser, Tobias¹⁰  Canbay, Ali¹¹  Berg, Christoph¹²  Trebicka, Jonel^9,13,14  Uschner, Frank E.^9,14  Chang, Johannes¹⁴  Mueller, Tobias²  Aehling, Niklas¹  Schmelzle, Moritz¹⁵  Splith, Katrin¹⁵  Lammert, Frank¹⁶  Lange, Christian M.^9,17  Sarrazin, Christoph^9,18  Trautwein, Christian⁵  Manns, Michael¹⁹  Haeussinger, Dieter²⁰  Pfeiffenberger, Jan²¹  Galle, Peter R.²²  Schmiedeknecht, Anett⁴  Berg, Thomas¹ 

[1] Univ Leipzig, Dept Med 2, Div Hepatol, Med Ctr, Liebigstr 21, D-04103 Leipzig, Germany

[2] Charite Univ Med Berlin, Dept Hepatol & Gastroenterol, Berlin, Germany

[3] Berlin Inst Hlth BIH, Berlin, Germany

[4] Univ Leipzig, Fac Med, Clin Trial Ctr ZKS Leipzig, Leipzig, Germany

[5] Aachen Univ Hosp, Dept Med 3, Aachen, Germany

[6] Univ Hosp Jena, Clin Internal Med 4, Jena, Germany

[7] St Georg Hosp, Clin Gastroenterol Hepatol & Endocrinol, Leipzig, Germany

[8] Martin Luther Univ Halle Wittenberg, Univ Hosp Internal Med 1, Halle, Germany

[9] Univ Hosp Frankfurt, Dept Internal Med 1, Frankfurt, Germany

[10] Univ Hosp Cologne, Clin Gastroenterol & Hepatol, Cologne, Germany

[11] Univ Hosp Ruhr Univ Bochum, Med Dept, Bochum, Germany

[12] Univ Hosp Tuebingen, Dept Internal Med &, Tubingen, Germany

[13] European Fdn Study Chron Liver Failure, Barcelona, Spain

[14] Univ Bonn, Dept Internal Med 1, Bonn, Germany

[15] Charite Univ Med Berlin, Dept Surg, Campus Charite Mitte Campus Virchow Klin, Berlin, Germany

[16] Saarland Univ, Dept Med 2, Med Ctr, Homburg, Germany

[17] Univ Hosp Essen, Clin Gastroenterol & Hepatol, Essen, Germany

[18] St Josefs Hosp Wiesbaden, Med Clin 2, Wiesbaden, Germany

[19] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany

[20] Heinrich Heine Univ Duesseldorf, Clin & Policlin Gastroenterol Hepatol & Infect Di, Dusseldorf, Germany

[21] Univ Hosp Heidelberg, Dept Gastroenterol & Hepatol, Heidelberg, Germany

[22] Univ Med Ctr Mainz, Dept Internal Med, Mainz, Germany

关键词: cirrhosis;    inflammation;    regeneration;    stem cell mobilization;    ACLF;    transplantation;    organ failure;   

DOI  :  10.1016/j.jhep.2021.07.033

来源: Elsevier

【 摘 要 】

Background & Aims: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. Methods: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 mu g/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary effi- cacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. Results: Patients treated with G-CSF had a 90-day transplant free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the GCSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. Conclusions: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. ClinicalTrials.gov number: NCT02669680 Lay summary: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies. (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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