Abstract
SummaryBackgroundResults of small-scale studies have suggested that stem-cell therapy is safe and effective in patients with liver cirrhosis, but no adequately powered randomised controlled trials have been done. We assessed the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) and haemopoietic stem-cell infusions in patients with liver cirrhosis.MethodsThis multicentre, open-label, randomised, controlled phase 2 trial was done in three UK hospitals and recruited patients with compensated liver cirrhosis and MELD scores of 11·0–15·5. Patients were randomly assigned (1:1:1) to receive standard care (control), treatment with subcutaneous G-CSF (lenograstim) 15 μg/kg for 5 days, or treatment with G-CSF for 5 days followed by leukapheresis and intravenous infusion of three doses of CD133-positive haemopoietic stem cells (0·2 × 106 cells per kg per infusion). Randomisation was done by Cancer Research UK Clinical Trials Unit staff with a minimisation algorithm that stratified by trial site and cause of liver disease. The coprimary outcomes were improvement in severity of liver disease (change in MELD) at 3 months and the trend of change in MELD score over time. Analyses were done in the modified intention-to-treat population, which included all patients who received at least one day of treatment. Safety was assessed on the basis of the treatment received. This trial was registered at Current Controlled Trials on Nov 18, 2009; ISRCTN, number 91288089; and the European Clinical Trials Database, number 2009-010335-41.FindingsBetween May 18, 2010, and Feb 26, 2015, 27 patients were randomly assigned to the standard care, 26 to the G-CSF group, and 28 to the G-CSF plus stem-cell infusion group. Median change in MELD from day 0 to 90 was −0·5 (IQR −1·5 to 1·1) in the standard care group, −0·5 (−1·7 to 0·5) in the G-CSF group, and −0·5 (−1·3 to 1·0) in the G-CSF plus stem-cell infusion group. We found no evidence of differences between the treatment groups and control group in the trends of MELD change over time (p=0·55 for the G-CSF group vs standard care and p=0·75 for the G-CSF plus stem-cell infusion group vs standard care). Serious adverse events were more frequent the in G-CSF and stem-cell infusion group (12 [43%] patients) than in the G-CSF (three [11%] patients) and standard care (three [12%] patients) groups. The most common serious adverse events were ascites (two patients in the G-CSF group and two patients in the G-CSF plus stem-cell infusion group, one of whom was admitted to hospital with ascites twice), sepsis (four patients in the G-CSF plus stem-cell infusion group), and encephalopathy (three patients in the G-CSF plus stem-cell infusion group, one of whom was admitted to hospital with encephalopathy twice). Three patients died, including one in the standard care group (variceal bleed) and two in the G-CSF and stem-cell infusion group (one myocardial infarction and one progressive liver disease).InterpretationG-CSF with or without haemopoietic stem-cell infusion did not improve liver dysfunction or fibrosis and might be associated with increased frequency of adverse events compared with standard care.FundingNational Institute of Health Research, The Sir Jules Thorn Charitable Trust.
Highlights
Chronic liver disease is a common cause of death globally, the incidence of which is rising due to a combination of alcohol consumption, obesity, and viral hepatitis.[1,2] the primary causes of injury, such as alcohol or viruses can be removed or treated, patients with cirrhosis often still have progression to liver decompensation leading to death.[3]
In the setting of liver cirrhosis, no improvement in liver dysfunction or markers of liver fibrosis occurred after the administration of granulocyte colony-stimulating factor (G-CSF) or G-CSF plus stem-cell infusions
Our findings show that G-CSF with or without haemopoietic stem-cell infusions does not improve liver function or reduce liver fibrosis
Summary
Chronic liver disease is a common cause of death globally, the incidence of which is rising due to a combination of alcohol consumption, obesity, and viral hepatitis.[1,2] the primary causes of injury, such as alcohol or viruses can be removed or treated, patients with cirrhosis often still have progression to liver decompensation leading to death.[3]. Evidence before this study We (JM/SJF) searched MEDLINE and Embase in July, 2013, to find clinical studies involving patients with liver disease (any language) who had received autologous cellular therapy. Abstracts were assessed by two independent reviewers and the full text versions of studies that were relevant were analysed. Bibliographies of these papers and reviews were studied, along with clinical trial websites (www.clinicaltrialresults.org and www.controlled-trials.com/ ukctr) and abstract books from international liver conferences for the past 3 years. Studies chosen had to contain patients with chronic liver disease, who had received autologous stem cells (any route) along with outcome data covering safety and feasibility as a principal outcome. Given the lack of randomised controlled studies, all trial designs were considered
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