Determinants of Relapse Risk After BMT for ALL

描述（由申请人提供）：造血干细胞移植（HSCT）是复发性或难治性急性淋巴细胞白血病（ALL）患者的主要挽救策略，可为部分患者提供长期疾病控制。不幸的是，大多数患者失败，复发仍然是失败的最常见原因。此处拟定的研究将使用从入组儿童肿瘤组ASCT 0431的患者中获得的标本。ASCT 0431是一项全国性随机III期研究，比较了两种旨在控制移植物抗宿主病（GVHD）的方案（标准与西罗莫司），并检验了mTOR抑制剂西罗莫司将在最小残留疾病点控制ALL，从而降低复发风险并提高生存率的假设。HSCT后复发的机制分为两大类：1）抗白血病治疗未能控制疾病; 2）MRD逃避同种异体免疫监视（GVL效应）的能力。我们假设，西罗莫司将通过消除或抑制HSCT后GVL可能因不成熟的免疫重建而缺失的期间残留的ALL来改善ALL的同种异体HSCT的结局，从而提供足够的GVHD控制而不降低GVL效应。以这种方式改善HSCT结果的方法将是移植和抗白血病治疗的重大进展。这些集中和综合的生物学研究将评估西罗莫司抗白血病效应和GVL在III期试验关键环境中直接用于接受定义的HSCT治疗和GVHD预防的复发性ALL儿童中的相对重要性，对于这些儿童，可获得初始复发的原始细胞样本。我们将实现两个特定目的：1）评估西罗莫司对患者PBMC和ALL原始细胞的影响。2)评估西罗莫司为基础的GVHD预防对GVL效应的影响。这项工作与该机构的使命直接相关，因为它旨在改善移植结果，在III期研究的背景下研究这种药物的作用机制，并提高复发性ALL患者的治愈率。Lay摘要。我们对最常见的儿童白血病有很好的治疗方法，称为ALL。但是，如果疾病复发（复发），大多数儿童将无法生存。这项研究将研究一种用于骨髓移植的新药西罗莫司如何有助于防止患者复发，并研究它如何在细胞中起作用以防止这一问题。

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.