Targeted Therapy for Lymphoid Malignancies

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是最常见的成人白血病，目前的治疗方法无法治愈。此外，某些CLL患者亚群，包括del（17p13.1）和患有ZAP-70未甲基化（ZAP-70+）疾病的患者对治疗反应不佳，总生存期较短。与CML不同，针对单一疾病特异性融合激酶的靶向治疗是可能的，在CLL中没有确定单一疾病特异性靶点。然而，最近的研究已经确定了b细胞受体（BCR）信号，包括pi3激酶，NF-？B和MAPK/ERK在CLL发生疾病扩张的淋巴结和骨髓腔室中组成性活跃，表明这可能是CLL的潜在靶点。此外，患有ZAP-70+疾病的患者具有增强的BCR信号。近端BCR信号导致布鲁顿无球蛋白血症酪氨酸激酶（Btk）的激活，该激酶在小鼠或人类中因突变或缺失而丢失，主要产生b细胞缺陷。基于此，我们首先研究并证明了口服生物可利用的、不可逆的Btk抑制剂ibrutinib （PCI-32765）促进直接凋亡，抑制细胞增殖，并阻断对CLL细胞存活重要的微环境基质信号。我们的团队与Pharmacyclics公司密切合作，在CLL中进行ibrutinib的第一阶段Ib/II期研究，其中90%的患者有临床获益。治疗耐受性良好，复发患者1年无进展生存率估计为86%，独立于del(17p)， ZAP-70+疾病患者的预后得到改善。该建议建立在伊鲁替尼早期经验的基础上，对复发性CLL患者进行了更明确的II期试验，其中包括一组单独的del（17p13.1）患者，包括药理学实验，旨在确定最可能通过伊鲁替尼单药治疗获得持久缓解的患者亚群，并研究12个月后未被该治疗消除的CLL细胞的特征。我们提案的具体目标包括：1)进行依鲁替尼的II期临床试验，以确定具有del（17p13.1）和缺乏del（17p13.1）的患者的反应和2年PFS，以及该药物作为持续治疗的长期毒性；2)进行基线和系列药效学研究，以确定传统的基因组特征、选择的BCR激活标记物和miR标记物表达的变化是否可预测疗效和2年PFS；3)从参加本试验和较早完成的单药伊鲁替尼试验的患者样本中进行研究，以确定12个月未从血液中清除的肿瘤细胞的生物学特征和消除这些肿瘤细胞的药理学策略。在完成本提案后，我们将确定伊鲁替尼对复发性del (17p13.1) CLL的疗效，同时还将确定该药物和肿瘤的单药活性预测特征

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is incurable with current therapies. Additionally, certain subsets of CLL patients including del(17p13.1) and those with ZAP-70 un- methylated (ZAP-70+) disease do not respond well to therapy and have a shorter overall survival. Unlike CML, where targeted therapy toward a single disease-specific fusion kinase is possible, in CLL there has been no single disease-specific targets identified. Recent studies, however, have identified B-cell receptor (BCR) signaling including the PI3-kinase, NF-?B, and MAPK/ERK are constitutively active in the lymph node and bone marrow compartment of CLL where disease expansion occurs suggesting that this may be a potential target in CLL. Additionally, patients with ZAP-70+ disease have enhanced BCR signaling. Proximal BCR signaling results in activation of the Bruton agammaglobulinemia tyrosine kinase (Btk) and genetic loss of this kinase by mutation or deletion in mice or humans produces predominately a B-cell defect. Based upon this, we were first to pursue and demonstrate that the orally bioavailable, irreversible Btk inhibitor ibrutinib (PCI-32765) promotes direct apoptosis, inhibits cell proliferation, and blocks microenvironment stromal signals important to CLL cell survival. In conjunction our group has worked closely with Pharmacyclics to perform the first phase Ib/II study of ibrutinib in CLL where 90% of patients had clinical benefit. Therapy has been well tolerated and the estimated progression-free survival rate is 86% at 1 year in relapsed patients independent of del(17p) and improved outcome in those with ZAP-70+ disease. This proposal builds upon this early experience of ibrutinib by performing a more definitive phase II trial in relapsed CLL with a separate cohort of del(17p13.1) patients that includes pharmacodynamic experiments aimed at identifying subsets of patients most likely to gain durable remissions with ibrutinib monotherapy and also to study the features of CLL cells not eliminated with this treatment at 12 months. The specific aims of our proposal include: 1) To perform a phase II clinical trial of ibrutinib to determine the response and 2-year PFS among patients having versus lacking del(17p13.1) and the long-term toxicity of this agent administered as a continuous therapy; 2) To perform baseline and serial pharmacodynamic studies to determine if traditional genomic features, select BCR activation markers, and changes in miR marker expression are predictive for response and 2-year PFS; and 3) To perform studies derived from samples from patients participating in both this and the earlier completed single agent ibrutinib trial to determine the biologic features of tumor cells not cleare from the blood by 12 months and pharmacologic strategies to eliminate these. At completion of this proposal, we will have determined the efficacy of ibrutinib in relapsed del (17p13.1) CLL while also identifying features predictive of single agent activity of this agent and also of tumor cells not effectively eliminated by ibrutinib. These will guide future combination studies with Ibrutinib that has great potential to completely change the treatment paradigm of CLL.