B-CLL Biology: Impact of Combination Therapy

B-慢性淋巴细胞白血病(B-CLL)是北美最常见的白血病。由于累积发病率继续上升，对这一目前无法治愈的疾病的认识和治疗有很大的必要。为了实现这一目标，我们希望通过各种实验室方法产生关于B-CLL中白血病B细胞克隆的更多有价值的相关信息。从代表进展性B-CLL典型临床反应的不同类型的B-CLL患者中获得克隆的信息是很重要的。为了实现这一目标，我们将使用化疗和单抗的独特组合，以顺序方式研究进展性疾病的B-CLL患者。具体地说，我们将用5-他汀类/环磷酰胺和Rituxan治疗B-CLL患者，最多治疗6个周期。因为我们相信这项试验将产生大量有反应的患者，我们可能会有至少三个重要的B-CLL患者队列来研究白血病B细胞克隆的关键生物学特征。由于使用这种组合方法的初步研究显示，总体临床缓解率(94%)和完全缓解率(60%)很高，这种治疗策略为我们提供了独特的机会，以确定作为反应性疾病、原发难治性疾病和反应性但持续性疾病患者亚群基础的生物学特征。需要研究的生物学参数包括B-CLL的凋亡和/或耐药性水平以及观察到的血管生成水平，因为这三个因素都有可能显着改变患者对治疗或疾病复发的初始反应。为了补充这些重点研究，我们还将使用白血病B细胞的基因表达谱。这种方法将使我们能够研究更多可能影响细胞凋亡、耐药性和血管生成的基因的表达水平。此外，这种广泛的方法将有助于识别可能解释疾病异质性和对这种特定疗法的反应的意想不到或新的基因。为了进行基因分析，它打算使用淋巴芯片，它已经显示了细分B-CLL克隆的挑衅性结果。然而，在这项研究中，我们将通过使用Lymphy芯片平台和更广泛的Affymetrix平台来扩大我们的表达谱分析的范围。最后，我们打算将上述生物学数据的收集与突变状态(即生殖系与体细胞突变型克隆)联系起来，因为我们和其他人有数据表明，即使在有反应的B-CLL患者中，生殖系B细胞克隆也具有显著的化疗耐药性和早期复发。全面阐明B-CLL中白血病细胞的相关生物学特性，将有助于设计针对残留的白血病B细胞的治疗策略，从而最终实现对这种疾病的治疗。

B-chronic lymphocytic leukemia (B-CLL) is the most common leukemia in North America. Since the cumulative incidence continues to rise there is a significant need for advances in the understanding and treatment of this currently incurable disease. To accomplish this goal we wish to generate additional valuable, relevant information about the leukemic B cell clones in B-CLL with a variety of laboratory approaches. It is important to obtain this information on clones from B-CLL patients who represent the differing types of clinical responses typically seen in progressive B-CLL. To accomplish that goal we will study in a sequential fashion B-CLL patients with progressive disease using a unique combination of chemotherapy and monoclonal antibodies. Specifically, we will treat B-CLL patients with pentostatin/cyclophosphamide and Rituxan for up to 6 cycles of therapy. Because we believe that this trial will generate significant numbers of responding patients we will likely have at least three important cohorts of B-CLL patients to study critical biologic features of the leukemic B cell clones. Because preliminary studies using this combination approach have demonstrated high rates of overall clinical response (94 percent) and complete response (60 percent), this treatment strategy presents us with the unique opportunity to identify biological features that underlie responsive disease, primary refractory disease, and responsive but persistent disease patient subsets. The biologic parameters to be studied include the level of B-CLL apoptosis and/or drug resistance and the level of angiogenesis observed since all three of these factors have the potential to significantly alter either initial patient response to therapy or disease relapse. To complement these focused studies, we will also employ gene expression profiling of the leukemic B cells. This approach will allow us to study the expression levels of a much larger number of genes that could impact on apoptosis, drug resistance and angiogenesis. In addition, this broad approach will facilitate the identification of unanticipated or novel genes that may explain disease heterogeneity and response to this specific therapy. To do the gene profiling it is intended to use the lymphochip which has shown provocative results for subdividing B-CLL clones. However in this study we will expand the scope of our expression profiling by using the Lymphochip platform in concert with the much broader Affymetrix platform. Finally we intend to relate the collection of biologic data described above to the mutational status (i.e. germline versus somatic mutation type clone) since we and others have data that germline type B cell clones have significant resistance to chemotherapy and early relapse even within responding B-CLL patients. The complete elucidation of the relevant biologic features of the leukemic cell in B-CLL is certain to be helpful for devising strategies that will target the residual leukemic B cells, thereby ultimately achieving cures for this disease.