Impact of Chemo-Immunotherapy in Relapsed/Refactory B-CLL

描述（由申请人提供）：在这种目前无法治愈的疾病中，对白血病CLL B细胞克隆的生物学的理解有很大的需要。为了解决这一问题，我们设计了一项联合化疗试验，利用两种已知具有重要组织部位特异性影响的单克隆抗体。利妥昔单抗和Campath似乎与化疗协同作用，识别CLL B细胞上的不同表面分子，并从不同的器官隔室中去除CLL白血病负荷。我们期望这种化学免疫疗法（CIT）方法在显著百分比（尽管不是全部）的复发患者中产生完全（CR）结节性PR或部分应答（PR）。在本提案中，我们希望对进入本试验的CLL患者进行相关实验室研究。我们将通过各种实验室方法获得关于B-CLL中白血病B细胞克隆的有价值的相关信息。我们的方法将允许我们a）监测临床应答者的白血病CLL B细胞负荷的最小残留水平及其T细胞库状态，和B）研究生物学特征的关联，其允许详细阐述风险分层参数并开始开发预测应答的预后模型。因此，对于发生CR的患者，我们将使用包括流式细胞术和定量聚合酶链反应测定的检测方法监测微小残留病（MRD）检测。这将用于确定临床CR伴或不伴MRD检测是否为CLL患者带来临床优势。由于CIT方法可能会给这些已经受损的患者带来免疫缺陷，因此我们打算通过使用流式和CDR 3谱型分析评估血液T细胞状态来监测其程度。我们将确定新风险分层参数的相关实验室检查包括：FISH可检测缺陷、免疫球蛋白可变重区突变状态、与CLL B细胞凋亡抗性相关的ZAP-70和VEGF自分泌途径以及这些患者骨髓组织的血管生成状态。有了这些信息，我们还将开发一个预后模型，可用于更准确的咨询和分层。最后，我们打算研究微小RNA在CLL B细胞克隆上的表达。这组新定义的基因有望揭示与疾病进展和用于定义更高风险疾病相关的基因。该基因集将被探索用于开发的CLL患者的预后模型。我们假设，这项试验将产生显着的反应，在更积极的CLL，我们将能够扩展的效用，选定的风险分层参数的CLL患者和产生进一步的洞察CLL B细胞的生物学。

DESCRIPTION (provided by applicant): There is a significant need for advances in the understanding of the biology of the leukemic CLL B cell clones in this currently incurable disease. To address this, we have designed a combination chemotherapy trial utilizing two monoclonal antibodies known to have important tissue site specific impact. Rituximab and Campath, appear to synergize with chemotherapy, recognize different surface molecules on CLL B cells, and effect removal of the CLL leukemic burden from separate organ compartments. We expect this chemoimmunotherapy (CIT) approach to generate complete (CR) nodular PR or partial responses (PR) in a significant percentage, albeit not all, of relapsed patients. In this proposal, we wish to perform correlative laboratory studies on the CLL patients entering this trial. We will generate valuable, relevant information about the leukemic B cell clones in B-CLL with a variety of laboratory approaches. Our approach will allow us to a) monitor the minimal residual level of leukemic CLL B cell burden for clinical responders and their T cell repertoire status and b) study the association of biologic features, which permit elaboration of risk stratification parameters and begin to develop a prognostic model that predict response. Thus for patients who experience a CR, we will monitor for minimal residual disease (MRD) detection using detection methods that include both flow cytometry and a quantitative polymerase chain reaction assay. This will be done to ascertain if a clinical CR with or without MRD detection confers clinical advantage to the CLL patients. Because the CIT approach is likely to confer immune deficiency to these already compromised patients, we intend to monitor the extent of this by assessing blood T cell status using both flow and CDR3 spectratype analysis. The correlative laboratory tests we will determine for novel risk stratification parameters include; FISH detectable defects, immunoglobulin variable heavy region mutational status, ZAP-70 and VEGF-based autocrine pathways related to apoptosis resistance of CLL B cells and the angiogenesis status of marrow tissue in these patients. With this information we will also develop a prognostic model that can be used for more accurate counsel and stratification. Finally we intend to study microRNA expression on the CLL B cell clones. This newly defined set of genes promises to uncover genes that relate to both disease progression and use in definition of more high risk disease. This gene set will be explored for use in the developed prognostic model for CLL patients. We hypothesize that this trial will generate significant responses in more aggressive CLL, that we will be able to extend the utility of selected risk stratification parameters for CLL patients and generate further insight into the biology of CLL B cells.