Improving cardiovascular outcomes in polycythaemia by risk stratification and targeted therapy.

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What is polycythaemia?Polycythaemia is a cancer of the bone marrow and blood. It causes people to make too many red cells which make the blood thicker and less able to travel through blood vessels. It can also cause people to make too many white cells and platelets, which do not work quite like healthy blood cells. People can live with polycythaemia for many years, but the cause of major medical problems and early death is increased risk of blood clots: heart attacks, strokes, and blockages in the deep veins of the leg (deep vein thrombosis) and in the blood vessels of the lung (pulmonary embolus). In the last 15 years there has been great progress in understanding what causes polycythaemia. It is usually caused by a change in the JAK2 gene which causes the bone marrow to produce too many blood cells. How is polycythaemia treated? There is no cure for polycythaemia and so the main aim of treatment is to reduce the risk of developing a blood clot. This is done by giving every patient low-dose aspirin daily to make the platelets less sticky; and to reduce the number of red cells by regular venesection to remove excess blood (similar to blood donation). People who are felt to be at particularly high risk of blood clots are additionally prescribed chemotherapy drugs (hydroxyurea and interferon) to try to reduce the number of excess blood cells. Despite this treatment, the risk of developing a blood clot remains high: about 1 in 20 people at 1 year and 1 in 5 people by 4 years.What is unknownWe currently only have a basic understanding of who is at the highest risk of having a blood clot, the mechanisms underlying the increased risk of blood clots in polycythaemia, and how different treatments might work to reduce the risk of blood clots. If we knew more about these things, then we could give more intensive targeted treatment to the people who are most likely to develop a blood clot in order to reduce this blood clot risk yet minimise side-effects of treatment. What will I do?A large clinical trial is planned to look at a novel drug called ruxolitinib, which targets the causative JAK2 gene, in 600 patients with polycythaemia and to compare the impact of ruxolitinib to standard therapy (hydroxyurea, interferon). Patients will receive the drugs for 3 years and be monitored closely. Any blood clots will be recorded and the numbers compared for the different treatments. I will collect additional blood samples, both before and after the drugs are started, and measure how sticky the platelets and white cells are, as well as how sticky the blood is overall. I will find out whether these results can predict whether or not the patient will develop a blood clot. I will do most of these tests in everyone who consents for the clinical trial in the UK (about 300 patients), however in a smaller number of patients, recruited locally, I will also request blood for additional novel tests to help further understand the mechanisms of blood clots in these patients. Finding out more about the mechanisms will help identify new targets for treatment. Why is this research important? This project brings together scientists and clinicians who are world leaders within polycythaemia, with experts in blood clotting. Together we will better understand who is at highest risk of developing blood clots, why, and how current treatments affect this. In the future this will help us to offer patients at highest risk of blood clots more intensive and more specific treatment, with fewer side-effects, so that fewer people with polycythaemia suffer major complications including death from blood clots. We will share the research results widely as they may be applicable to other diseases, including other cancers; and so will hopefully also help to reduce the likelihood of blood clots for people with diseases other than polycythaemia in the future.