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

什么是红细胞增多症？红细胞增多症是一种骨髓和血液的癌症。它会导致人们产生太多的红细胞，从而使血液变稠，减少通过血管的能力。它还会导致人们产生太多的白细胞和血小板，它们的工作原理与健康的血细胞不太一样。人们可以与红细胞增多症生活多年，但重大医疗问题和过早死亡的原因是血栓的风险增加：心脏病发作、中风和腿部深静脉堵塞(深静脉血栓形成)和肺血管堵塞(肺血栓)。在过去的15年里，在了解导致红细胞增多症的原因方面有了很大的进步。它通常是由JAK2基因的变化引起的，这种变化导致骨髓产生太多的血细胞。如何治疗红细胞增多症？目前还没有治愈红细胞增多症的方法，因此治疗的主要目的是降低形成血栓的风险。做到这一点的方法是每天给每位患者服用低剂量的阿司匹林，以降低血小板的粘性；并通过定期采集静脉血来减少红细胞数量，以清除多余的血液(类似于献血)。被认为是血栓风险特别高的人会被额外开出化疗药物(羟基脲和干扰素)，试图减少多余的血细胞数量。尽管进行了这种治疗，但血栓形成的风险仍然很高：1岁时约为1/20人，4年后为1/5人。尚不清楚的是，我们目前只基本了解谁患血栓的风险最高，红细胞增多症导致血栓风险增加的潜在机制，以及不同的治疗方法如何降低血栓风险。如果我们对这些事情有更多的了解，那么我们就可以对最有可能发生血栓的人进行更密集的靶向治疗，以降低这种血栓的风险，同时将治疗的副作用降到最低。我将做什么？一项大型临床试验计划在600名红细胞增多症患者中观察一种名为ruxolitinib的新药，它针对致病的JAK2基因，并比较ruxolitinib与标准疗法(羟基脲、干扰素)的影响。患者将接受为期3年的药物治疗，并受到密切监测。任何血栓都会被记录下来，并对不同治疗方法的数字进行比较。我会收集更多的血样，包括开始服药前和服药后的血样，并测量血小板和白细胞的粘性，以及血液的总体粘性。我会弄清楚这些结果是否能预测患者是否会出现血栓。我将在同意在英国进行临床试验的每个人(约300名患者)中进行大部分这些测试，但在当地招募的一小部分患者中，我还将要求血液进行额外的新颖测试，以帮助进一步了解这些患者的血栓机制。更多地了解这些机制将有助于确定新的治疗靶点。为什么这项研究很重要？该项目汇集了在红细胞增多症领域处于世界领先地位的科学家和临床医生，以及血液凝固方面的专家。我们将一起更好地了解谁是发展成血栓的最高风险，为什么，以及目前的治疗方法如何影响这一点。在未来，这将有助于我们为血栓风险最高的患者提供更密集和更具体的治疗，副作用更少，从而使更少的红细胞增多症患者遭受包括血栓死亡在内的主要并发症。我们将广泛分享研究结果，因为它们可能适用于其他疾病，包括其他癌症；因此，希望也将有助于降低未来患有除红细胞增多症以外的疾病的人发生血栓的可能性。

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.