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。它会导致人们产生过多的红细胞，使血液变厚，无法通过血管。它还会导致人们产生过多的白细胞和血小板，这些白细胞和血小板不像健康的血细胞那样起作用。患有红细胞增多症的人可以存活多年，但主要医疗问题和早期死亡的原因是血栓风险增加：心脏病发作、中风和腿部深静脉阻塞（深静脉血栓形成）和肺部血管阻塞（肺栓塞）。在过去的15年里，在了解导致红细胞增多症的原因方面取得了很大进展。它通常是由JAK2基因的变化引起的，这种变化导致骨髓产生过多的血细胞。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，所以治疗的主要目的是降低形成血栓的风险。这是通过每天给每位患者低剂量阿司匹林来降低血小板粘性来实现的；并通过定期的静脉切除去除多余的血液（类似于献血）来减少红细胞的数量。那些被认为有特别高血栓风险的人，还会额外开化疗药物（羟基脲和干扰素），试图减少多余血细胞的数量。尽管采用了这种治疗方法，但发生血栓的风险仍然很高：1年后约为1 / 20,4年后为1 / 5。目前，我们对哪些人患血栓的风险最高、红细胞增多症中血栓风险增加的机制以及不同的治疗方法如何降低血栓的风险只有基本的了解。如果我们对这些事情了解得更多，那么我们就可以对最有可能形成血栓的人进行更密集的有针对性的治疗，以减少血栓的风险，同时最大限度地减少治疗的副作用。我该怎么办？一项大型临床试验计划在600名多红细胞血症患者中观察一种名为ruxolitinib的新药，该药物针对JAK2致病基因，并比较ruxolitinib与标准治疗（羟基脲、干扰素）的影响。患者将接受3年的药物治疗并密切监测。任何血凝块都将被记录下来，并对不同治疗方法的血块数量进行比较。我会收集额外的血液样本，在药物开始之前和之后，并测量血小板和白细胞的粘性，以及血液的总体粘性。我将看看这些结果是否能预测病人是否会形成血栓。我将对所有同意在英国进行临床试验的人（约300名患者）进行大部分测试，但在本地招募的少数患者中，我也会要求他们进行额外的新测试，以帮助进一步了解这些患者的血凝块机制。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生血栓的最高风险人群，为什么，以及目前的治疗如何影响这一点。在未来，这将帮助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成果，因为它们可能适用于其他疾病，包括其他癌症；这也将有助于减少血块的可能性对于患有血球增多症以外的疾病的人来说。

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.