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: 8000049
• 负责人: Jorge E Cortes
• 金额: $ 139.09万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000049
• 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; Modality; Molecular; Newly Diagnosed; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phenotype; Polymerase; Progression-Free Survivals; Proteinase 3; Randomized; Refractory; Relapse; Residual Neoplasm; Residual Tumors; Resistance development; Staging; Testing; 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 therapeufic opfions for pafients with CML. Imafinib is standard therapy for CML, but neariy 20% of patients never achieve complete cytogenetic remission, and most have residual disease by polymerase chain reacfion, 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. Pafients 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 invesfigate 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-posifive cells, the third aim is to invesfigate whether JAK2 inhibition may have clinical activity in CML pafients 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 methylafion is associated with progression in CML. We will thus treat patients with blast phase CML with decitabine, a hypomethylating agent, and dasafinib to determine whether this combinafion 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改善CML患者的治疗方案。伊马非尼是 CML的标准治疗，但近20%的患者从未达到完全细胞遗传学缓解， 通过聚合酶链反应，大多数患者有残留疾病， 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， 伊马替尼治疗失败后的显著临床活性。第一个目的是确定达沙替尼或尼洛替尼是否可能 改善分子学应答，以及新感染患者的无事件和无进展生存期 诊断为慢性期CML患者将在两项平行研究之一中接受治疗， 目的提高12个月时的分子学缓解率.第二个目的是调查是否 免疫疗法，以PRI疫苗的形式，可以改善患者的分子反应， 伊马替尼治疗的残留疾病。因为干扰素可以提高蛋白酶3的表达， 具有该表型的患者将随机接受PRI和伊马替尼， 没有干扰素。主要目的是提高PRI疫苗的分子应答。基于 通过该授权产生的数据表明JAK 2在Bcr-Abl阳性细胞中的激活，第三个目的是 研究JAK 2抑制是否对TKI难治性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INCB 18424（JAK 2抑制剂）的II期试验。长期 计划是将这种药物与TKI结合使用。第四个目标是处理爆炸病人的问题 阶段，一组治疗效果不佳。达沙替尼诱导高应答率，但大多数 患者最终会复发。甲基化增加与CML进展相关。因此，我们将 对急变期CML患者使用地西他滨（一种低甲基化药物）和达沙替尼，以确定 联合用药可提高急变期CML的缓解率和持久性。总的来说，这个项目 可能会改善所有疾病阶段患者的长期结局，并使我们更接近 彻底根除CML。