Graft vs Host Disease (GvHD) is a common complication for many patients during their recovery after a stem cell transplant. It’s caused by small differences between the new immune system and the patient’s other cells. This means the growing immune system may harm some of these cells because it sees them as ‘different’. It can affect different parts of the body but commonly affects the skin, gut and liver in the early stages after transplant, and can affect any part of the body later.
Steroids are often given to treat GvHD because they help stop the immune system from over-reacting. While this often helps to control GvHD, some patients become dependent on the steroids or the GvHD becomes resistant to treatment - so new treatments are needed.
In this article we look at three promising new GvHD drugs that were highlighted in our recent blog with Dr Fiona Dignan, a consultant in haemato-oncology at Manchester Royal Infirmary. They are currently being tested in clinical trials around the world.
What is a clinical trial?
When a new treatment is designed and developed in a lab it needs to be tested with patients to confirm that it’s safe and effective. Clinical trials generally have three phases that involve an increasingly larger number of patients.
Phase I: Small studies that help determine how well a drug can be tolerated and the side effects it causes.
Phase II: Longer studies that usually involve hundreds of patients. They help to determine the correct dose of drug and sometimes compare it to the existing best treatment available.
Phase III: These studies often involve thousands of patients across multiple hospitals. They are randomised, which means patients don’t know if they receive the currently approved treatment or the one being tested.
Ruxolitinib – acute GvHD
Ruxolitinib has already been approved to treat several conditions that affect bone marrow and red blood cells. It blocks proteins that control inflammation and other immune responses. This has led to the idea that it might also be effective against GvHD.
It was first tested in two small studies that involved patients who had developed steroid resistant GvHD after a stem cell transplant for various blood cancers. Across both studies over 80% of all patients responded well to Ruxolitinib, with less than 10% of them having a GvHD relapse during the study. Ruxolitinib has now been given ‘breakthrough designation therapy’ status in the USA – meaning that because the results were so promising, it can be given to patients while larger studies are carried out.
Additional clinical trials are now being performed, including the phase II REACH1 trial where Ruxolitinib is being compared to available GvHD treatments, and another trial where it’s being used as a cream to treat skin GvHD.
Ibrutinib – chronic GvHD
Ibrutinib is the first drug to be approved in the USA to treat chronic GvHD that doesn’t respond to standard first line treatments. In a similar way to Ruxolitinib, it works by stopping a protein called Bruton's tyrosine kinase (BTK), that normally helps to activate immune responses.
Its approval as a fellow ‘breakthrough designation therapy’ was based on a phase II clinical trial where two thirds of patients showed at least a partial response to Ibrutinib. Most of these patients were also able to lower their steroid intake because of the treatment.
Azacitidine – chronic GvHD
Azacitidine is an established chemotherapy agent that is used to treat certain blood cancers including acute myeloid leukaemia (AML) and chronic myelomonocytic leukaemia (CMML) as well as myelodysplastic syndrome (MDS).
At low doses it targets proteins involved in gene regulation, which stops cells growing uncontrollably. At higher doses it becomes toxic to abnormal blood cells in the bone marrow, meaning that it could help control the immune responses that cause GvHD.
The AZTEC trial, that’s determining the effectiveness of Azacitidine, is now recruiting patients to its second phase. These patients have developed GvHD that doesn’t respond to steroids following a stem cell transplant. It follows on from a successful phase I trial that showed, following Azacitidine treatment, GvHD could be more effectively treated with steroids in all the patients that took part.
You can find out more information on the AZTEC trail here.
If you are interested in participating in a clinical trial, you should discuss your options with your medical team. Unfortunately, it’s not always possible to join a trial because they have defined patient criteria in place. This is to give the trial the best possible chance of succeeding.
Anthony Nolan supports the IMPACT partnership that co-ordinates clinical trials across the UK that focus on improving stem cell transplantation and its side effects. For more details please visit the IMPACT website.