Targeted Therapy for Lymphoid Malignancies

描述(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，目前的治疗方法是无法治愈的。此外，CLL患者的某些亚群，包括del(17p13.1)和ZAP-70非甲基化(ZAP-70+)疾病患者，对治疗的反应不好，总生存期较短。与慢性粒细胞白血病不同的是，在慢性粒细胞白血病中，针对单一疾病特异性融合激酶的靶向治疗是可能的，而在慢性粒细胞白血病中，没有发现单一疾病特异性靶点。然而，最近的研究发现，B细胞受体信号通路包括PI3K、NF-κB和MAPK/ERK在淋巴细胞性淋巴细胞性白血病的淋巴和骨髓中具有结构性的活性，提示这可能是淋巴细胞性淋巴细胞性白血病的一个潜在靶点。此外，ZAP-70+疾病患者的bcr信号增强。近端的BCR信号导致Bruton无丙种球蛋白血症酪氨酸激酶(BTK)的激活，在小鼠或人类中，该激酶的突变或缺失导致的遗传损失主要导致B细胞缺陷。在此基础上，我们首次探索并证明了口服生物利用型、不可逆BTK抑制剂伊布鲁替尼(pCI-32765)可促进细胞直接凋亡、抑制细胞增殖、阻断对慢性淋巴细胞性白血病细胞存活至关重要的微环境间质信号。同时，我们小组与Pharmacclics公司密切合作，开展了伊布鲁替尼在慢性淋巴细胞性白血病中的第一阶段Ib/II研究，90%的患者获得了临床益处。治疗耐受性良好，在不依赖DEL(17P)的复发患者中，估计一年的无进展存活率为86%，而那些ZAP-70+疾病患者的结果有所改善。这项建议建立在ibrutinib的这一早期经验的基础上，通过在一组单独的del(17p13.1)患者队列中对复发性CLL进行更明确的II期试验，其中包括旨在确定最有可能通过ibrutinib单一疗法获得持久缓解的患者亚群的药效学试验，并研究12个月后未被这种治疗消除的CLL细胞的特征。我们建议的具体目标包括：1)进行ibrutinib的II期临床试验，以确定在Del(17p13.1)和缺乏Del(17p13.1)的患者中的疗效和2年PFS，以及作为持续治疗给予该药的长期毒性；2)进行基线和系列药效学研究，以确定传统基因组特征、选择BCR激活标记和miR标记表达的变化是否可以预测疗效和2年PFS；以及3)从参加这项试验和之前完成的单剂伊布鲁替尼试验的患者的样本中进行研究，以确定12个月后血液中未清除的肿瘤细胞的生物学特征和消除这些肿瘤细胞的药物策略。在完成这项建议后，我们将确定ibrutinib在复发性del(17p13.1)CLL中的疗效，同时还确定了预测该药物和未被ibrutinib有效消除的肿瘤细胞的单药活性的特征。这些将指导未来与伊布鲁替尼的联合研究，这将具有完全改变CLL治疗范式的巨大潜力。

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-κB, 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.