Chemo-Immunotherapy in Relapsed/Refactory B-Chronic Lymphocytic Leukemia

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抗。利妥昔单抗和CamPath似乎与化疗有协同作用，识别CLL B细胞上的不同表面分子，并有效地从单独的器官间隔中去除CLL白血病的负担。我们期望这种化学免疫治疗(CIT)方法能在很大比例的复发患者中产生完全(CR)结节PR或部分反应(PR)。在这项建议中，我们希望对参加这项试验的CLL患者进行相关的实验室研究。我们将通过各种实验室方法在B-CLL中产生有关白血病B细胞克隆的有价值的相关信息。我们的方法将使我们能够a)监测临床应答者的白血病CLL B细胞负荷的最低残留水平和他们的T细胞库状态，以及b)研究生物学特征的关联，这使得我们能够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，对于经历CR的患者，我们将使用包括流式细胞术和定量聚合酶链式反应分析在内的检测方法来监测微小残留病(MRD)的检测。这样做是为了确定有或没有MRD检测的临床CR是否为CLL患者提供了临床优势。由于CIT方法可能会使这些已经受损的患者出现免疫缺陷，我们打算通过使用Flow和CDR3谱型分析评估血液T细胞状态来监测这种情况的程度。我们将为新的风险分层参数确定的相关实验室测试包括：FISH可检测到的缺陷、免疫球蛋白可变重区突变状态、ZAP-70和基于血管内皮生长因子的自分泌通路与CLL B细胞的凋亡抵抗相关，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测模型，可以用于更准确的咨询和分层。最后，我们打算研究microRNA在CLL B细胞克隆上的表达。这组新定义的基因有望发现与疾病进展有关的基因，并用于定义更高风险的疾病。该基因集将被用于已开发的CLL患者预后模型。我们假设这项试验将在更具侵袭性的CLL中产生显著的反应，我们将能够扩展CLL患者选择的风险分层参数的实用性，并对CLL B细胞的生物学产生进一步的洞察。

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.