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.

该项目的主要目的是确定CML患者改善的治疗选择。伊马替尼是CML的标准疗法，但近20％的患者从未实现完全的细胞遗传学缓解，大多数患者患有聚合酶链反应的残留疾病，而达到缓解的患者中有10-15％最终进展。在伊马替尼衰竭后，更有效的酪氨酸激酶抑制剂（TKI）（例如dasatinib和nilotinib）具有显着的临床活性。第一个目的是确定达沙替尼或尼洛替尼是否可以改善分子反应，以及新诊断的慢性期CML患者的无事件和无进展的生存。将在两项平行研究之一中接受患者的治疗，其主要目的是提高12个月时分子反应率的主要目标。第二个目的是研究以PRI疫苗形式的免疫疗法是否可以改善伊马替尼治疗中残留疾病最小的残留疾病患者的分子反应。由于干扰素可能会改善蛋白酶3的表达，因此有或没有干扰素，患有该表型的患者将随机地接受PRI和伊马替尼。主要目的是改善PRI疫苗的分子反应。基于通过该赠款的数据提示在BCR-ABL阳性细胞中激活JAK2的数据，第三个目的是研究JAK2抑制是否可能在CML患者对TKI难治性的临床活性中是否具有临床活性。我们将对至少2个TKI失败的患者进行INCB18424（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。第四个目标涉及爆炸阶段患者的问题，爆炸阶段的患者是一群具有可用治疗的结果。达沙替尼诱导高反应率，但大多数患者最终复发。甲基化增加与CML的进展有关。因此，我们将用Decitabine，一种甲基化剂和达沙替尼治疗爆炸期CML患者，以确定这种组合是否可以提高爆炸相CML中反应的速率和持久性。总体而言，该项目可能会改善患有疾病各个阶段的患者的长期结局，并使我们更加完全消除CML。