Improving the Outcome of Patients with Chronic Myeloid Leukemia Through Medi

通过医疗改善慢性粒细胞白血病患者的预后

• 批准号: 8722321
• 负责人: Jorge E Cortes
• 金额: $ 134.49万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722321
• 关键词: 2-tyrosine; Blast Phase; Cells; Chronic Myeloid Leukemia; Chronic-Phase Myeloid Leukemia; Clinical; Cytogenetics; Dasatinib; Data; Decitabine; Disease; Disease remission; Event; Failure; Goals; Grant; Imatinib; Immunotherapy; Interferons; JAK2 gene; Lead; Malignant - descriptor; Methylation; Modality; Molecular; Newly Diagnosed; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phenotype; Polymerase Chain Reaction; Progression-Free Survivals; Proteinase 3; Randomized; Refractory; Relapse; Residual Neoplasm; Residual Tumors; Resistance development; Staging; Testing; Therapeutic; Treatment Efficacy; Tyrosine Kinase Inhibitor; Vaccines; base; cell mediated lymphocytolysis test; immunoregulation; improved; inhibitor/antagonist; response; success

The main objective of this project is to identify improved therapeutic options for patients with CML. Imatinib is standard therapy for CML, but nearly 20% of patients never achieve complete cytogenetic remission, and most have residual disease by polymerase chain reaction, and 10-15% of those who achieve remission eventually progress. More potent tyrosine kinase inhibitors (TKI) such as dasatinib and nilotinib have significant clinical activity after imatinib failure. The first aim is to determine whether dasatinib or nilotinib may improve the molecular response, and event-free and progression-free survival of patients with newly diagnosed chronic phase CML. Patients will be treated in one of two parallel studies with the primary objective to improve the molecular response rate at 12 months. The second aim is to investigate whether immunotherapy, in the form of PRI vaccine, can improve molecular responses of patients with minimal residual disease on imatinib therapy. Because Interferon may improve the expression of proteinase 3 from which PRI is derived, patients with this phenotype will be randomized to receive PRI and imatinib, with or without interferon. The primary objective is to improve the molecular response with PRI vaccine. Based on data originated through this grant suggesting activation of JAK2 in Bcr-Abl-positive cells, the third aim is to investigate whether JAK2 inhibition may have clinical activity in CML patients refractory to TKI. We will conduct a phase 2 trial of INCB18424, a JAK2 inhibitor, in patients who failed at least 2 TKI. The long-term plan is to use this agent in combination with TKI. The fourth aim deals with the problem of patients with blast phase, a group with dismal outcome with available therapy. Dasatinib induces high response rates but most patients eventually relapse. Increased methylation is associated with progression in CML. We will thus treat patients with blast phase CML with decitabine, a hypomethylating agent, and dasatinib to determine whether this combination may improve the rate and durability of responses in blast phase CML. Overall, this project may lead to improved long-term outcome for patients with all phases ofthe disease and get us closer to complete eradication of CML.

该项目的主要目标是为慢性粒细胞白血病患者确定改进的治疗方案。伊马替尼是CML的标准治疗方法，但近20%的患者从未达到细胞遗传学完全缓解，大多数患者通过聚合酶链式反应产生残留疾病，获得缓解的患者中有10%-15%最终取得进展。更有效的酪氨酸激酶抑制剂(TKI)，如达沙替尼和尼洛替尼，在伊马替尼失效后具有显著的临床活性。第一个目标是确定达沙替尼或尼洛替尼是否可以改善新诊断的慢性期CML患者的分子反应以及无事件和无进展生存率。患者将接受两项平行研究中的一项，主要目标是在12个月后提高分子应答率。第二个目的是调查以PRI疫苗形式进行的免疫治疗是否可以改善伊马替尼治疗的微小残留病患者的分子反应。由于干扰素可以改善PRI来源的蛋白水解酶3的表达，具有这种表型的患者将随机接受PRI和伊马替尼治疗，加或不加干扰素。主要目的是改善PRI疫苗的分子反应。基于通过这项拨款获得的数据表明，在bcr-Abl阳性细胞中JAK2被激活，第三个目的是调查JAK2抑制是否对TKI无效的CML患者具有临床活性。我们将在至少2次TKI失败的患者中进行JAK2抑制剂INCB18424的2期试验。长期计划是将该代理与TKI结合使用。第四个目标涉及急变期患者的问题，这是一组结果令人沮丧的可用的治疗方法。达沙替尼的应答率很高，但大多数患者最终会复发。甲基化增加与慢性粒细胞白血病的进展有关。因此，我们将用去甲基化药物地西他滨和达沙替尼治疗急变期CML患者，以确定这种组合是否可以提高急变期CML的反应速度和持久性。总体而言，该项目可能会改善所有疾病阶段患者的长期结果，并使我们更接近完全根除CML。