Combination Therapy in B-Chronic Lymphocytic Leukemia

描述(由申请人提供)：在前一批赠款期间，我们完成了一项针对以前未接受治疗的B-CLL患者的试验，针对该试验，我们联合应用了五肽(P)、环磷酰胺(C)和利妥昔单抗(R)(聚合酶链式反应)。我们观察到，在遗传高风险的CLL队列中，许多残留疾病阴性患者的有效率为91%，但我们继续完善这些风险分层参数与临床结果之间的关系，以便更全面地评估生物风险因素与疾病结果之间的重要关系，包括无进展(PFS)和总体(OS)生存时间。事实证明，在老年患者(70岁)和肌酐清除量和/或表现状态降低的患者中，PCR方案同样有效，耐受性良好。这是例外，因为其他CIT方案通常被证明对老年和表现不佳的患者都是无法忍受的。最后，这种方案已被证明具有最小的骨髓抑制和非常低的重大感染发生率。尽管有这些进展，CR或NPR中的患者仍然存在可检测到的MRD；一些患者已经复发，部分患者仅实现了PR。我们相信，PCR方案提供了一个极好的平台，可以从中调整和改进基于CIT的治疗。为了改进聚合酶链式反应方案，我们建议增加抗血管内皮生长因子导向抗体(贝伐单抗[阿瓦斯丁])。与CIT中的其他药物相比，该单抗具有不重叠的作用机制，并为CLL B细胞开辟了一条重要的生存途径。基于血管内皮生长因子的信号似乎以自分泌和旁分泌的方式培养CLL B细胞，以促进CLL B细胞的存活。这种治疗可能有助于使肿瘤血管正常化，使组织部位体验到更有效的药物输送，并有可能加强治疗。事实上，抗血管内皮生长因子治疗已经被证明在其他恶性肿瘤中提高了联合化疗的疗效。我们认为，这为治疗方案增加了一种更有针对性的方法，不仅可以促进CR率的提高，还有助于消除可检测到的MRD。结合这项研究，我们建议继续评估已经存在的新的预后因素与我们团队发现的新的预后因素之间的关系，以完善用于预测疾病反应的预后模型。因此，我们的两个目标包括：1)确定在未经治疗的B-CLL中，加用贝伐单抗是否可以提高已知的五氧他丁/环磷酰胺联合利妥昔单抗的临床疗效。此外，在这项试验中，我们将继续研究已建立的和新的预后参数与临床结果的相关性。最后，我们将评估治疗后立即不同程度的MRD作为延长的PFS的预测替代标记物的重要性的前瞻性验证。2)探讨加入抗血管内皮生长因子药物对慢性淋巴细胞性白血病患者体内、外血管生成的影响及其与临床疗效的关系。公共卫生意义：慢性淋巴细胞性白血病是我国一种非常常见的白血病，目前是无法治愈的。由于至少70%的患者将需要治疗，以提高生活质量，避免疾病并发症和增加存活率，我们致力于在CLL中测试联合疗法。这项提议正在测试一种独特的药物和单抗组合的能力，我们相信，这种组合有可能在毒性最小的进展性CLL患者中诱导高水平的临床反应。由于这种联合方法的力量，我们将评估通过使用成像研究(即CT扫描)评估结节和脾大小来确定应答水平的完整程度的可行性，以及通过敏感的流式细胞术患者是否可以有低到阴性的微小残留病。此外，我们正在测试我们的能力，以筛选出可能需要更积极治疗的更高风险疾病的患者，以及继续探索独特的独立于阶段的预后因素，这些因素可用于特定患者的敏感和特定预后，这些患者将接受CLL的联合治疗。

DESCRIPTION (provided by applicant): In the previous grant period, we completed a trial in patients with previously untreated B-CLL for which we administered the combination pentostatin (P), cyclophosphamide (C) and rituximab (R) (PCR). We observed a 91% response rate in a genetically high-risk CLL cohort with many negative residual disease patients, but we continue to refine the relationship between these risk-stratification parameters and clinical outcome in order to more completely evaluate important relationships between biologic risk factors and disease outcome, including progression-free (PFS) and overall (OS) survival times. The PCR regimen proved equally effective and well-tolerated in elderly patients (age > 70) and those with reduced creatinine clearance and/or performance status. This is exceptional given that other CIT regimens often prove intolerable for both elderly and poor performance status patients. Finally, this regimen has proven to have minimal marrow suppression and very low incidence of major infections. Despite these advances, patients in CR or nPR continue to have detectable MRD; some patients have relapsed and a subset of patients only achieved a PR. We believe the PCR regimen offers an excellent platform from which to modulate and improve CIT-based therapy. In an effort to improve on the PCR regimen, we propose adding the anti-VEGF directed antibody (bevacizumab [Avastin]). This monoclonal antibody has a non-overlapping mechanism of action compared to the other drugs in CIT, and exploits an important survival pathway for CLL B cells. VEGF-based signaling appears to nurture CLL B-cells in an autocrine and paracrine fashion to promote the survival of CLL B-cells. This treatment may help normalize the tumor vasculature and make the tissue site experience more efficient drug delivery with potential for treatment enhancement. Indeed, anti-VEGF therapy has been shown to enhance the efficacy of combination chemotherapy in other malignancies. We believe this adds a more targeted approach to the therapeutic regimen and can facilitate not only an improvement in the CR rate, but also help eradicate detectable MRD. In concert with this study we propose to continue to assess the relationship of the novel prognostic factors already in place as well as newer prognostic factors discovered by our team in order to refine the prognostic models used for prediction of disease response. Thus our two aims include: 1) To determine if the known clinical efficacy of the combination of pentostatin/cyclophosphamide with rituximab can be enhanced with the addition of bevacizumab in previously untreated B-CLL. In addition we will continue to study the association of established and novel prognostic parameters for association with clinical outcome in this trial. Finally we will assess the prospective validation of the importance of different degrees of MRD immediately post-therapy as a predictive surrogate marker of extended PFS. 2) Explore the impact of adding an anti-VEGF agent on in vitro and in vivo alterations of angiogenesis in CLL patients and whether they correlate with clinical response to PCR-B therapy. PUBLIC HEALTH RELEVANCE: Chronic Lymphocytic Leukemia is a very common leukemia in this country and is currently incurable. Because at least 70 percent of all patients will require treatment in order to have an enhanced quality of life, avoidance of complications of the disease and increased survival, we are committed to testing combination therapies in CLL. This proposal is testing the ability of a unique combination of drugs and monoclonal antibodies that, we believe, have the potential to induce high levels of clinical responses with minimal toxicity for CLL patients with progressive disease. Because of the power of this combination approach we will assess the feasibility of defining how complete the response level can be by both assessing node and spleen size using imaging studies (i.e., CT scans) and if patients can have low to negative minimal residual disease by sensitive flow cytometry. In addition, we are testing our ability to select out patients with more high risk disease who may need more vigorous therapy as well as to continue to explore unique stage independent prognostic factors that can be used for sensitive and specific prognosis in a given patient who will receive combination therapy for CLL.