Determinants of Relapse Risk After BMT for ALL

描述(申请人提供)：造血干细胞移植(HSCT)被用作复发或难治性急性淋巴细胞白血病(ALL)患者的主要抢救策略，为一些患者提供长期的疾病控制。不幸的是，大多数患者失败了，复发仍然是最常见的失败原因。这里提出的研究将利用从ASCT0431儿童肿瘤学小组登记的患者获得的标本。ASCT0431是一项全国性的随机第三阶段研究，比较了两种旨在控制移植物抗宿主病(GVHD)的方案(标准方案和基于西罗莫司的方案)，并测试了mTOR抑制剂西罗莫司将在最小残留疾病的点上控制ALL的假设，从而降低复发风险和提高存活率。HSCT后复发的机制分为两大类：1)抗白血病治疗失败，无法控制疾病；2)MRD逃避同种异体免疫监视的能力(GVL效应)。我们推测，西罗莫司将通过消除或抑制HSCT后残留的ALL来改善ALL的预后，此时GVL可能由于免疫重建不成熟而消失，从而在不降低GVL效应的情况下提供足够的GVHD控制。以这种方式改善HSCT结局的方法将是移植和抗白血病治疗的重大进步。这些集中和综合的生物学研究将在第三阶段试验的关键背景下，评估西罗莫司抗白血病效果和GVL直接在接受特定HSCT疗法和GVHD预防的复发ALL治疗的儿童中的相对重要性，并且这些儿童可以获得最初复发的原始样本。我们将实现两个具体目标：1)评估西罗莫司对患者PBMC和所有原始细胞的影响。2)评价西罗莫司预防移植物抗宿主病对移植物抗宿主病疗效的影响。这项工作与该机构的使命直接相关，因为它寻求改善移植结果，在III期研究的背景下研究这种药物的作用机制，并提高复发ALL患者的治愈率。Laye摘要。我们有非常好的治疗方法来治疗最常见的儿童白血病，称为ALL。然而，如果疾病复发(复发)，大多数儿童将无法存活。这项研究将研究一种用于骨髓移植的新药西罗莫司如何帮助防止患者复发，并在细胞中研究它如何预防这一问题。

DESCRIPTION (provided by applicant): Hematopoietic stem cell transplantation (HSCT) is used as the major salvage strategy for patients with relapsed or refractory acute lymphoblastic leukemia (ALL), providing long-term disease control for some patients. Unfortunately, the majority of patients fail and relapse remains the most frequent cause of failure. The studies proposed here will utilize specimens obtained from patients enrolled on Children's Oncology Group ASCT0431. ASCT0431 is a nationwide randomized phase III study comparing two regimens (standard vs. sirolimus-based) designed to control graft vs. host disease (GVHD), and testing the hypothesis that the mTOR inhibitor sirolimus will control ALL at a point of minimal residual disease and thus decrease relapse risk and improve survival. Mechanisms of post-HSCT relapse fall into two broad categories: 1) the failure of anti-leukemic therapy to control disease; and 2) the ability of MRD to escape allogeneic immunosurveillance (the GVL effect). We hypothesize that sirolimus will improve the outcome of allogeneic HSCT for ALL by eliminating or suppressing residual ALL during the period post-HSCT when GVL may be absent due to immature immune reconstitution, thus providing adequate GVHD control without decreasing the GVL effect. A method to improve HSCT outcome in this fashion would be a major advance in transplantation and antileukemia therapy. These focused and integrated biological studies will assess the relative importance of sirolimus antileukemic effect and GVL directly in children treated for relapsed ALL with defined HSCT therapies and GVHD prophylaxis, and for whom blast samples from the initial relapse are available, in the critical setting of a Phase III trial. We will accomplish two Specific Aims: 1) Assess the impact of sirolimus on patient PBMC and on the ALL blasts. 2) Assess the impact of sirolimus-based GVHD prophylaxis on the GVL effect. The work is directly relevant to the mission of the agency because it seeks to improve transplant outcome, study the mechanisms of action of this agent in the context of a phase III study, and improve cure rates for patients with relapsed ALL. Lay Summary. We have very good treatments for the most common childhood leukemia, called ALL. However, if the disease comes back (relapse), most of the children will not survive. This research will look how a new drug used in bone marrow transplant, called sirolimus, may help prevent relapse in patients and study in the cells how it may act to prevent this problem.