The use of Minimal Residual Disease detection to improve treatment outcome in childhood acute lymphoblastic leukaemia

白血病是最常见的儿童癌症，约占所有病例的35%。尽管进行了强化治疗，该疾病仍经常在骨髓中复发，尽管在诊断时根据一些标准将儿童分为预后良好组和预后不良组，但两组都有复发。现有证据表明，在预后良好的组中，早期发现治疗反应不良，并在癌症负担处于较低水平时实施替代治疗，极有可能提高患者的生存。我们的实验室开发了一种新的分子遗传技术，可以检测和定量非常低水平的残留白血病，具有很高的灵敏度和特异性。该项目的主要目标是开展一项临床试验，在治疗的早期阶段使用这种测试程序，对测试结果不佳的患者进行更密集的治疗，看看这是否能提高生存率。此外，该项目还旨在调查已知在药物解毒中起作用的一系列基因。这些药物代谢基因存在许多自然发生的变异，有证据表明，特定的变异或模式可能影响癌症对治疗的反应。因此，我们将研究存在于大量白血病队列中的遗传模式，并将这些模式与治疗反应联系起来。预计这些研究将有助于确定白血病儿童最适当的治疗策略。因此，该项目对白血病儿童的治疗管理具有重大意义，并有可能直接有助于提高这种最常见的儿童癌症的生存率。

Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Available evidence suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the cancer burden is at a low level, has a high likelihood of improving patient survival. The failure to respond well to treatment is assessed by a novel molecular genetic technique developed in our laboratory that can detect and quantitate very low levels of residual leukaemia with great sensitivity and specificity. The major goal of this project is to conduct a clinical trial in which this testing procedure is used at an early stage of treatment, and patients who have a bad result on this test, will be given more intensive treatment to see if this improves survival rates. In addition, the project is also directed towards investigating a range of genes known to have a role in drug detoxification. A number of naturally occurring variations exist for these drug metabolising genes and there is evidence suggesting that specific variations or patterns may influence a cancer's response to treatment. We will therefore examine the genetic patterns present in a large cohort of leukaemias and correlate these patterns with response to treatment. It is anticipated that these studies will help define the most appropriate treatment strategies for children with leukaemia. This project therefore has major implications for the therapeutic management of children with leukaemia and has the potential of contributing directly to the improved survival of this most common of childhood cancers.