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

复发/难治性 B 慢性淋巴细胞白血病的化学免疫治疗

• 批准号: 8117698
• 负责人: Neil E Kay
• 金额: $ 28.26万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117698
• 关键词: Achievement; Address; Antibody Therapy; Apoptosis; B-Lymphocytes; Biological; Biological Assay; Biology; Blood; Cells; Cellular biology; Chemotherapy-Oncologic Procedure; Chromosome abnormality; Chronic Lymphocytic Leukemia; Clinical; Combination Drug Therapy; Combined Modality Therapy; Counseling; Cyclophosphamide; Defect; Detection; Detection of Minimal Residual Disease; Development; Disease; Disease Outcome; Disease Progression; Evaluation; Excision; Flow Cytometry; Gene Expression; Genes; Genetic; Goals; Immune; Immunoglobulins; Immunotherapy; Interphase; Investigation; Karyotype; Laboratories; Laboratory Study; Leukemic Cell; MabCampath; Marrow; Measures; Metaphase; Methods; MicroRNAs; Modeling; Molecular; Monitor; Monoclonal Antibodies; Mutation; Oligonucleotides; Organ; Outcome; Pathway interactions; Patients; Pattern; Pentostatin; Polymerase Chain Reaction; Population; Process; Progression-Free Survivals; Refractory; Refractory Disease; Regimen; Relapse; Residual Neoplasm; Residual state; Resistance; Risk; Risk Factors; Site; Stratification; Surface; T-Lymphocyte; Testing; Time; Tissues; Toxic effect; Vascular Endothelial Growth Factors; Work; ZAP-70 Gene; angiogenesis; autocrine; base; chemotherapy; clinical efficacy; cohort; design; experience; high risk; insight; leukemia; novel; partial response; phase 2 study; prognostic; response; rituximab

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.

描述（由申请人提供）：对于目前无法治愈的白血病CLL - B细胞克隆的生物学理解有很大的需求。为了解决这个问题，我们设计了一种联合化疗试验，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细胞的不同表面分子，并从不同的器官室中去除CLL白血病负担。我们期望这种化学免疫治疗（CIT）方法在很大比例（尽管不是全部）复发患者中产生完全（CR）结节性PR或部分缓解（PR）。在本提案中，我们希望对进入本试验的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获得有关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细胞负荷的最小残留水平及其T细胞库状态；B)研究生物学特征的关联，这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反应试验在内的检测方法监测最小残留病（MRD）检测。这样做是为了确定是否有或没有MRD检测的临床CR对CLL患者具有临床优势。由于CIT方法可能会使这些已经受损的患者产生免疫缺陷，我们打算通过使用血流和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检测缺陷、免疫球蛋白可变重区突变状态、ZAP-70和vegf自分泌通路与CLL - B细胞凋亡抵抗和骨髓组织血管生成状态相关。有了这些信息，我们还将开发一种预后模型，可用于更准确的咨询和分层。最后，我们打算研究microRNA在CLL B细胞克隆中的表达。这组新定义的基因有望揭示与疾病进展和高风险疾病定义相关的基因。该基因集将被用于开发的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效用，并进一步了解CLL B细胞的生物学。

项目成果

Karyotype-specific microRNA signature in chronic lymphocytic leukemia.

• DOI: 10.1182/blood-2009-06-229211
• 发表时间: 2009-10
• 期刊: Blood
• 影响因子: 20.3
• 作者: R. Visone;L. Rassenti;A. Veronese;C. Taccioli;S. Costinean;B. Aguda;S. Volinia;M. Ferracin;J. Palatini;Veronica Balatti;H. Alder;M. Negrini;T. Kipps;C. Croce

Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia.

• DOI: 10.1001/jama.2010.1919
• 发表时间: 2011-01-05
• 期刊: JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
• 影响因子: 120.7
• 作者: Fabbri, Muller;Bottoni, Arianna;Shimizu, Masayoshi;Spizzo, Riccardo;Nicoloso, Milena S.;Rossi, Simona;Barbarotto, Elisa;Cimmino, Amelia;Adair, Brett;Wojcik, Sylwia E.;Valeri, Nicola;Calore, Federica;Sampath, Deepa;Fanini, Francesca;Vannini, Ivan;Musuraca, Gerardo;Dell'Aquila, Marie;Alder, Hansjuerg;Davuluri, Ramana V.;Rassenti, Laura Z.;Negrini, Massimo;Nakamura, Tatsuya;Amadori, Dino;Kay, Neil E.;Rai, Kanti R.;Keating, Michael J.;Kipps, Thomas J.;Calin, George A.;Croce, Carlo M.
• 通讯作者: Croce, Carlo M.