Professor Thomas Berg and Dr Cornelius Engelmann from the University Hospital Leipzig speak to SciTech Europa about the potential of G-CSF as a treatment option for acute-on-chronic liver failure (ACLF).
Chronic liver diseases can culminate in acute-on-chronic liver failure which is characterised by a loss of function of multiple organs. Acute-on-chronic liver failure currently has only few treatment options, meaning that many patients die as a result.
The GRAFT study at the University Hospital Leipzig, Germany, is evaluating the G-CSF hormone which is a potential future treatment option for acute-on-chronic liver failure in a multi-centre, German clinical trial.
Dr Cornelius Engelmann and Dr Cornelius Engelmann spoke to SciTech Europa about the challenge of treating acute-on-chronic liver failure including the organ injury, the potential benefits of treating ACLF with the G-CSF hormone, and the progress of the GRAFT trial to test this.
What are the current challenges involved with treating acute-on-chronic liver failure (ACLF)?
Acute-on-chronic liver failure is a severe disease which causes many fatalities in Europe and all over the world. We are currently about to understand the mechanisms leading to this sudden worsening of liver function and loss of organ function. Yet, most often we are not able to treat patients adequately. One reason is that ACLF is a highly dynamic disease which passes though different stages. An initial systemic inflammatory response, which appears as a sepsis-like syndrome, causes major organ injuries. This stage transits gradually into a immune-compromised stage in which the bacterial defence system is severely suppressed, similar to patients taking immunosuppressive medications. It is obvious that both stages require different therapeutic approach, though we are not yet able to identify the individual needs for patients.
It is therefore of major interest to find a treatment which targets both stages at the same time.
What is the impact of systemic inflammation on organ injury in ACLF?
Systemic inflammation is a crucial mechanism leading to organ injury. There are two major groups of molecules present in patients with cirrhosis. The first are endotoxins which arise from bacteria translocating from the intestine (‘pathogen-associated molecular patterns’ (PAMPs). The major molecule here is lipopolysaccharide (LPS). Endotoxins are able to induce cell death directly in organ tissue. This process releases a second type of molecule, which is called ‘damage-associated molecular patterns’ (DAMPs). These two types of molecules, when secreted into the circulation of cirrhosis patients, both induce systemic inflammatory response which further aggravates organ injury and sepsis-like haemodynamic alterations, creating a deadly vicious circle.
What are the benefits of the granulocyte colony stimulating factor (G-CSF), and could you outline its potential role in the clinical treatment of ACLF?
G-CSF is an endogenous hormone that mobilises both immunmodulatory (appeasing) haematopoietic stem cells and neutrophil granulocytes from the bone marrow, which are essential for bacterial clearance. It is released in everyone, particularly in stressful situations or in the event of inflammation, in order to respond to increase the body’s defence mechanisms. There is extensive experience in using recombinant G-CSF in patients with toxic bone marrow injury after chemotherapy as well as before stem cell transplantation. In ACLF, G-CSF is considered to act on both, it modulates the proinflammatory response syndrome leading to an more appropriate response to endotoxins and bacteria thereby reducing the organ injury and stabilising the functional properties responsible to clear bacteria from the circulation.
During the last five years, a few studies performed in Asia showed a marked effect of recombinant G-CSF in patients with ACLF. The results supported the hypothesis, that has its effect on both stages of ACLF. There was a marked improvement of survival, sometimes improving from 20% to nearly 80%. Moreover, this was accompanied by a significantly reduced risk of bacterial infection and infection related deaths.
What are the aims of the GRAFT study, and how has it been designed?
Until today, published data are limited to small monocentre studies performed in India. An independent confirmation of these results is therefore an absolutely necessity before this treatment can be introduced to the daily clinical praxis. We therefore designed the GRAFT study in 2013 aiming to enrol 292 patients. Patients are randomised into two groups – either standard of care or plus treatment with G-CSF over in total 26 days. Patients will be followed up for 360 days in order to test the efficacy of the drug but also to document potential complications which might develop with the treatment.
The primary end point of the study is 90 days of transplant-free survival. We are also measuring other end points, such as the improvement of the patient’s liver function, rate of infections and the development of malignant disease. In co-operation with the Charite Berlin, PD Dr. med. Moritz Schmelzle, we are also performing ancillary studies, which will help to understand the mechanisms how G-CSF acts in in ACLF.
What progress has the GRAFT study made towards treating ACLF, and what are your hopes for the future of your study and the ancillary studies?
We have now recruited over 150 patients to the GRAFT study, which is over half of the total patients required. In comparison to the number of patients included in all of the studies published in India, which have been 50-70 patients in each study, this is already now the largest study so far and it is also the only multi-centre study.
We are about to perform an interim analysis of the first 150 patients which will be due in January 2019. This will provide us with the first results about how G-CSF is working in a robust study setting.
Regardless of the result, the GRAFT study is a crucial milestone in the clinical application of G-CSF as regardless of the outcome it will provide a strong argument either for or against using G-CSF in ACLF.