Combination Therapy in B-Chronic Lymphocytic Leukemia

描述（由申请人提供）：在之前的资助期内，我们在先前未经治疗的B-CLL患者中完成了一项试验，我们给药戊他汀(P)，环磷酰胺(C)和利妥昔单抗(R) （PCR）。我们观察到在具有许多阴性残留疾病的遗传高风险CLL队列中有91%的缓解率，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，以便更完整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（OS）生存时间。事实证明，PCR方案在老年患者（50 ~ 70岁）和肌酐清除率降低和/或运动状态降低的患者中同样有效且耐受性良好。考虑到其他CIT方案对老年人和表现不佳的患者往往是无法忍受的，这是一个例外。最后，该方案已被证明具有最小的骨髓抑制和非常低的主要感染发生率。尽管有这些进展，CR或nPR患者仍然有可检测的MRD；一些患者复发，一部分患者仅达到PR。我们相信PCR方案为调节和改进基于cit的治疗提供了一个极好的平台。为了改进PCR方案，我们建议添加抗vegf定向抗体（贝伐单抗[阿瓦斯汀]）。该单克隆抗体与CIT中的其他药物相比，具有不重叠的作用机制，并且开辟了CLL B细胞的重要生存途径。基于vegf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肿瘤血管系统的正常化，并使组织部位更有效地给药，具有增强治疗的潜力。事实上，抗vegf治疗已被证明可以提高其他恶性肿瘤联合化疗的疗效。我们相信这为治疗方案增加了更有针对性的方法，不仅可以促进CR率的提高，而且有助于根除可检测的MRD。为了配合这项研究，我们建议继续评估已经存在的新预后因素以及我们团队发现的新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中加入贝伐单抗是否可以增强戊他汀/环磷酰胺联合利妥昔单抗的已知临床疗效。此外，我们将在本试验中继续研究已建立的和新的预后参数与临床结果的关联。最后，我们将评估治疗后不同程度的MRD作为延长PFS的预测替代标志物的重要性的前瞻性验证。2)探讨添加抗vegf药物对CLL患者体内外血管生成改变的影响，以及是否与临床对PCR-B治疗的反应相关。公共卫生相关性：慢性淋巴细胞白血病是一种非常常见的白血病，目前无法治愈。因为至少70%的患者需要治疗以提高生活质量，避免疾病并发症和提高生存率，我们致力于测试CLL的联合治疗。该方案旨在测试一种独特的药物和单克隆抗体组合的能力，我们相信，这种组合有可能对进行性CLL患者产生高水平的临床反应，并且毒性最小。由于这种联合方法的强大功能，我们将通过影像学研究（即CT扫描）评估淋巴结和脾脏大小来评估确定反应水平完整程度的可行性，以及患者是否可以通过流式细胞术检测低至阴性的最小残留疾病。此外，我们正在测试我们的能力，以选择出可能需要更有力治疗的高风险疾病患者，并继续探索独特的分期独立预后因素，这些因素可用于接受CLL联合治疗的特定患者的敏感和特异性预后。

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.