P1314 : Granulocyte colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: a multicenter randomized trial (GRAFT STUDY)

Abstract Background & Aims Acute-on-chronic liver failure (ACLF) is a syndrome that develops in patients with decompensated liver cirrhosis and which is characterized by organ failure and poor short-term prognosis. Based on positive results from small single center studies, Granulocyte-Colony Stimulating Factor (G-CSF) is being widely used in the treatment of ACLF patients. The aim of that study was to evaluate the safety and efficacy of G-CSF in patients with ACLF. Methods In this multicenter, prospective, controlled, open-label phase 2 study, 176 patients with ACLF defined by the EASL-CLIF criteria were randomized to receive G-CSF (at a dose 5 μg/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 efficacy endpoint was the 90-day transplant free survival analysed by Cox regression modeling. The key secondary endpoints were the overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores (model of end-stage liver disease score (MELD) and CLIF-C OF score) during the entire observation period. Results Patients treated with G-CSF had a 90-day transplant free survival of 34.1% compared to 37.5% in the SMT group with a hazard ratio (HR) of 1.05 (95%CI 0.711; 1.551) (p=0.805). The 360-day transplant free survival with a HR of 0.998 [95%CI 0.697; 1.430 (p=0.992)] and overall survival with a HR of 1.058 [95%CI 0.727; 1.548 (p=0.768)] also did not differ between groups. G-CSF did not improve the CLIF-C OF score (p=0.757), MELD score (p=0.884) or the occurrence of infections (p=0.251). In subgroups of patients without infections [p=0.883], with alcohol related ACLF [p=0.875], or with ACLF defined by the APASL criteria [p=0.405] G-CSF also failed to improve survival. Sixty-one serious adverse events (SAE) were reported in the G-CSF+SMT group and 57 SAEs in the SMT group. In total, seven 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, this first multicenter, controlled trial failed to show a significant beneficial effect of G-CSF in treating patients with ACLF, and therefore, suggests G-CSF should not be used as a standard treatment for ACLF. Lay Summary G-CSF was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled trial phase 2 trial which showed that G-CSF in not improving survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies. ClinicalTrails.gov number NCT02669680.